Pyridine derivative

ABSTRACT

As a result, the inventors have found that (2R)-3-amino-2-{[4-(substituted pyridine)-2-yl]methyl}-2-hydroxy-propanoic acid derivatives have excellent P-LAP inhibitory activity. The inventors have evaluated antidiuretic effects in water-loaded rats and have found that the compounds increase endogenous AVP levels by inhibiting P-LAP and consequently reduce urine production. The present invention therefore provides compounds expected to be used as an agent for treating nocturia based on P-LAP inhibition.

TECHNICAL FIELD

The present invention relates to a novel pyridine derivative or a saltthereof which is useful as a pharmaceutical, specifically apharmaceutical for treating nocturia, and to a pharmaceutical containingsuch a compound as an active ingredient.

BACKGROUND ART

Nocturia is a lower urinary tract symptom defined as “the complaint thatthe individual has to wake at night one or more times to void”(Neurourol Urodyn 2002; 21: 167-178). Nocturia prevalence increases withage (J Urol 2010; 184: 440-446), and major patients with nocturia areolder adults. It impairs quality of life (QOL) in that it disrupts sleep(Eur Urol 2010; 57: 488-498) and increases risk of fracture. Causes ofnocturia are global polyuria, nocturnal polyuria, reduced bladdercapacity, and sleep disorders, but in many patients nocturia isconsidered to be multifactorial (Eur Urol 2012; 62: 877-890). Nocturnalpolyuria is defined as nocturnal urine volume greater than 33% of the24-hour urine volume and is present in about 80% of the patients withnocturia (J Urol 2011; 186: 1358-1363).

Arginine-vasopressin (hereinafter, abbreviated as AVP) is anantidiuretic hormone that is biosynthesized and secreted in thehypothalamic-pituitary gland axis, and is a peptide consisting of nineamino acids. AVP receptors are classified into three subtypes: V1a, V1b,and V2. Known major pharmacological actions of AVP in the periphery arevasoconstriction through the V1a receptor, and antidiuresis through theV2 receptor. AVP acts on the renal tubules to promote renal waterreabsorption, decreasing the urine volume. For this reason, decreasednocturnal AVP secretion with age is assumed to be a cause of increasednocturnal urine volume (J Int Med 1991; 229: 131-134, BJU Int 2004; 94:571-575).

Stimulation of the V2 receptor is expected to improve nocturia.Desmopressin (hereinafter, abbreviated as dDAVP) is a selective V2receptor agonist used for treating patients with nocturia, and isreported to decrease nocturnal urine volume and the number of nocturnalvoids, resulting in an increased duration of initial undisturbed sleep(J Urol 2013; 190: 958-964, and J Urol 2013; 190: 965-972).Unfortunately, V2 receptor agonists theoretically induce fluid retentionand increase risks of hyponatremia. It is reported that V2 receptoragonists should be administered with caution and monitoring of serumsodium level to older adults who are the majority of patients withnocturia (Neurourol urodyn 2004; 23: 302-305).

Placental leucine aminopeptidase (hereinafter, abbreviated as P-LAP) isan enzyme that degrades L-leucine-β-naphthylamide, oxytocin, and AVP(Arch Biochem Biophys 1992; 292: 388-392), and was cloned as anaminopeptidase by Rogi et al. in year 1996 (J Biol Chem 1996; 271:56-61). The insulin-regulated aminopeptidase (hereinafter, abbreviatedas IRAP) cloned by Keller et al. from rat epididymal fat pads hashomology of 87% to human P-LAP. The IRAP is subsequently suggested to bean aminopeptidase that cleaves AVP and reported to be a rat homolog ofhuman P-LAP (J Biol Chem 1995; 270: 23612-23618, Am J Physiol EndocrinolMetab 2007; 293: E1092-E1102). Angiotensin IV (AT₄) receptor isolatedfrom bovine adrenal is also suggested to be an IRAP as a result ofbiochemical and pharmacological studies (J Biol Chem 2001; 276:48623-48626).

Experiments using P-LAP knockout mice indicate that administration ofAVP in wild type mice and P-LAP knockout mice results in much reductionof 24-h urine volume in P-LAP knockout mice, although no significantdifference is observed in the 24-h urine volume between the wild typeand P-LAP knockout mice. It suggests the possible involvement of P-LAPin regulation of the urine volume through degradation of AVP (NPL 1).

Compounds represented by Formula (A) below are reported to be IRAPinhibitors useful as a therapeutic agent for dementia and diabetes, andthe like (PTLs 1 and 2).

wherein X is O, NR′ or S, and other symbols are defined as in PTLs 1 and2.

Tripeptide analogs of AT₄ with 13- to 14-membered ring structureexhibits excellent IRAP inhibitory activity (NPL 2).

However, no antidiuretic agent or therapeutic agents for nocturia basedon a mechanism mediated by P-LAP (or IRAP) has been reported.

Under such circumstances, there exists need for a safe antidiureticagent that is suitable for treating nocturia.

CITATION LIST Patent Literature

-   [PTL 1] WO 2006/026832-   [PTL 2] WO 2009/065169

Non Patent Literature

-   [NPL 1] Life Sciences 84 (2009) 668-672-   [NPL 2] J Med Chem 2011; 54; 3779-3792

SUMMARY OF INVENTION Technical Problem

The present invention provides a compound useful as an active ingredientof a pharmaceutical composition, specifically a pharmaceuticalcomposition for treating nocturia.

Solution to Problem

The inventors have assumed that inhibition of nocturnal activity ofP-LAP, i.e. aminopeptidase that cleaves AVP, would maintain and/orincrease an endogenous AVP level to enhance the antidiuretic effect,which would contribute to a decreased number of nocturnal voids, andhave extensively studied compounds which inhibit P-LAP (including ratIRAP, a homolog of human P-LAP).

As a result, the inventors have found that a compound represented byFormula (I) below has excellent P-LAP inhibitory activity. The inventorshave evaluated antidiuretic effects in water-loaded rats and have foundthat the compound represented by Formula (I) increases endogenous AVPlevels by inhibiting P-LAP and consequently reduces urine production.Based on such findings, the inventors have accomplished the presentinvention.

The present invention relates to a compound represented by Formula (1)or a salt thereof, and a pharmaceutical composition comprising thecompound represented by Formula (I) or a salt thereof and an excipient:

wherein, X is O, S or NR⁴;

R⁴ is H, lower alkyl which optionally has one to five substituentsselected from the Group G¹, C₃₋₁₂ cycloalkyl which optionally has one tofive substituents selected from the Group G², -(lower alkylene)-(C₃₋₁₂cycloalkyl) which optionally has one to five substituents selected fromthe Group G², —C(O)-(lower alkyl which optionally has one to fivesubstituents selected from the Group G¹), —C(O)—(C₃₋₁₂ cycloalkyl whichoptionally has one to five substituents selected from the Group G²), or—C(O)-(lower alkylene)-(C₃₋₁₂ cycloalkyl which optionally has one tofive substituents selected from the Group G²), or R⁴ forms together withneighboring —NR¹, as —NR¹R⁴, a 4- to 8-membered nitrogen-containingsaturated heterocyclic group, wherein the nitrogen-containing saturatedheterocyclic group may be condensed with a benzene ring and optionallyhas one to five substituents selected from the Group G⁴;

R¹ is H, C₁₋₁₀ alkyl which optionally has one to five substituentsselected from the Group G¹, -(lower alkylene)-X¹¹-(lower alkyl whichoptionally has one to five substituents selected from the Group G¹),R¹¹, -(lower alkylene)-R¹¹, -(lower alkylene)-X¹¹—R¹¹, or -(loweralkylene)-X¹¹-(lower alkylene)-R¹¹;

R²'s are the same or different from each other, and are H, lower alkylwhich optionally has one to five substituents selected from the GroupG¹, halogen, OH, SH, —O-(lower alkyl), —O-(lower alkylene)-aryl,—O-aryl, —S-(lower alkyl), —S-(lower alkylene)-aryl, —S-aryl, —O-(lowerhalogenoalkyl), —C(O)-(lower alkyl), —S(O)₂-(lower alkyl), —S(O)-(loweralkyl), NO₂, —NH₂, —NH-(lower alkyl), —N(lower alkyl)₂, —NH-aryl,—N(lower alkyl)-aryl, —C(O)OH, —C(O)O-(lower alkyl), —CHO, —C(O)NH₂,—C(O)NH-(lower alkyl), —C(O)N(lower alkyl)₂, CN, -(loweralkylene)-X²¹-(lower alkyl which optionally has one to five substituentsselected from the Group G¹), C₃₋₁₂ cycloalkyl which optionally has oneto five substituents selected from the Group G², C₃₋₁₂ cycloalkenylwhich optionally has one to five substituents selected from the Group G²and which may be condensed with a benzene ring optionally having one tofour substituents selected from the Group G³, aryl which optionally hasone to five substituents selected from the Group G⁵, -(loweralkylene)-R²¹, -(lower alkylene)-X²¹—R²¹, or -(loweralkylene)-X²¹-(lower alkylene)-R²¹;

R³ is R³², -(lower alkylene)-X³¹—R³², -(lower alkenylene)-X³¹—R³², R³¹,-(lower alkylene)-R³¹, -(lower alkylene)-X³¹—R³¹, -(loweralkylene)-X³¹-(lower alkylene)-R³¹, -(lower alkenylene)-R³¹, -(loweralkynylene)-R³¹, or —CH=(saturated monocyclic heterocycle);

X¹¹, X²¹ and X³¹ are the same or different from each other, and are O orS(O)_(n), wherein n is 0, 1, or 2;

R¹¹, R²¹, and R³¹ are the same or different from each other, and areC₃₋₁₂ cycloalkyl which optionally has one to five substituents selectedfrom the Group G², C₃₋₁₂ cycloalkenyl which optionally has one to fivesubstituents selected from the Group G² and which may be condensed witha benzene ring optionally having one to four substituents selected fromthe Group G³, aryl which optionally has one to five substituentsselected from the Group G⁵, or mono- or bi-cyclic heterocyclic groupwhich optionally has one to five substituents selected from the GroupG⁵;

R³² is C₁₋₁₀ alkyl which optionally has one to five substituentsselected from the Group G¹, lower alkenyl which optionally has one tofive substituents selected from the Group G¹, or lower alkynyl whichoptionally has one to five substituents selected from the Group G¹;

R^(P) is H or an ester group and R⁶ is H; or R^(P) and R⁶ are linked toeach other to form, together with —O—C(═O)—C—O— to which they areattached, 2,2-di(lower alkyl)-4-oxo-1,3-dioxolane-5,5-diyl;

if R³ is C₁₋₁₀ alkyl which is optionally substituted by one to fivehalogens, —X—R¹ is optionally linked to any one of R²'s attached to apyridine ring to which —X—R¹ is also attached, to constitute a grouprepresented by any one of formulae —X^(b)—(CH₂)_(m)—Y—, —X^(b)—CH═CH—,—X^(b)—CH═N—, and —X^(b)—N═CH—, and form a heterocycle condensed withthe pyridine ring, wherein m is an integer of 1 to 3, X^(b) is O, S orNH, Y is CH₂, O, S or NH, and the heterocycle optionally has one to foursubstituents selected from the group consisting of: C₃₋₁₂ cycloalkylwhich optionally has one to five substituents selected from the GroupG²; -(lower alkylene)-(C₃₋₁₂ cycloalkyl which optionally has one to fivesubstituents selected from the Group G²); and the substituents definedin the Group G³; in replacement of one or more H atoms attached to thering atom(s) of the heterocycle;

—X—R¹ is optionally linked to R³ to form a group represented by formula—X—(C₅₋₁₅ carbon chain)-, wherein the C₅₋₁₅ carbon chain optionally hasone to two O or S atoms in replacement of C atom(s), optionally has oneto five unsaturated bonds, and optionally has one to five substituentsselected from the Group G⁴;

Group G¹ consists of halogen, OH, SH, —O-(lower alkyl), —O-(loweralkylene)-aryl, —O-aryl, —S-(lower alkyl), —S-(lower alkylene)-aryl,—S-aryl, —O-(lower halogenoalkyl), —C(O)-(lower alkyl), —C(O)-aryl,—S(O)₂-(lower alkyl), —S(O)-(lower alkyl), NO₂, —NH₂, —NH-(lower alkyl),—N(lower alkyl)₂, —NH-aryl, —N(lower alkyl)-aryl, —C(O)OH, —C(O)O-(loweralkyl), —CHO, —C(O)NH₂, —C(O)NH-(lower alkyl), —C(O)N(lower alkyl)₂,—C(O)NH-aryl, and CN;

Groups G² and G⁴ consist of the substituents in the Group G¹, loweralkyl which optionally has one to five substituents selected from theGroup G¹, —O—(C₂₋₃ alkylene)-O—, and —O—(C₃₋₄ alkylene)-;

Group G³ consists of the substituents in the Group G¹ and lower alkylwhich optionally has one to five substituents selected from the GroupG¹; and

Group G⁵ consists of: i) the substituents in the Group G¹; ii) loweralkyl, lower alkenyl and lower alkynyl, each of which optionally has oneto five substituents selected from the Group G¹; iii) -(loweralkylene)-O-(lower alkyl, lower alkenyl or lower alkynyl, whichoptionally has one to five substituents selected from the Group G¹); iv)C₃₋₁₂ cycloalkyl, and C₃₋₁₂ cycloalkenyl which may be condensed with abenzene ring optionally having one to four substituents selected fromthe Group G³, the C₃₋₁₂ cycloalkyl and the C₃₋₁₂ cycloalkenyl optionallyhave one to five substituents selected from the Group G²; v) aryl whichoptionally has one to five substituents selected from the Group G³; vi)mono- or bi-cyclic heterocyclic group which optionally has one to fivesubstituents selected from the Group G³; vii) -(lower alkylene)-R^(G);viii) -(lower alkylene)-O—R^(G); ix) —C(O)—R^(G); x) —C(O)—O—R^(G); xi)—C(O)—O-(lower alkylene)-R^(G); and xii) —S(O)₂—R^(G), wherein R¹¹'s arethe same or different from each other, and are C₃₋₁₂ cycloalkyl whichoptionally has one to five substituents selected from the Group G²,C₃₋₁₂ cycloalkenyl which optionally has one to five substituentsselected from the Group G² and which may be condensed with a benzenering optionally having one to four substituents selected from the GroupG³, aryl which optionally has one to five substituents selected from theGroup G³, or a mono- or bi-cyclic heterocyclic group which optionallyhas one to five substituents selected from the Group G³.

As used herein, if a symbol used in a chemical formula is also used inother chemical formula, identical symbols have the same definition,unless otherwise specified.

The present invention also relates to a pharmaceutical compositioncomprising the compound represented by Formula (I) or a salt thereof.The pharmaceutical composition encompasses an agent for treatingnocturia. The present invention also relates to a pharmaceuticalcomposition comprising the compound represented by Formula (I) or a saltthereof and an excipient.

The present invention also relates to use of the compound represented byFormula (I) or a salt thereof for production of a pharmaceuticalcomposition for treating nocturia, use of the compound represented byFormula (I) or a salt thereof for treating nocturia, the compoundrepresented by Formula (I) or a salt thereof for treating nocturia, anda method of treating nocturia comprising administering to a subject aneffective amount of the compound represented by Formula (I) or a saltthereof. As used herein, “subject” is a human or non-human animal inneed of a preventive or therapeutic treatment, and in one embodiment, ahuman in need of the preventive or therapeutic treatment.

Advantageous Effects of Invention

The compound represented by Formula (I) or a salt thereof has inhibitoryactivity against P-LAP, i.e. the AVP-metabolizing enzyme, and maintainsand/or increases an endogenous AVP level to reduce urine production.Such a compound thus is expected to be used as an agent for treatingnocturia, and is also expected to be used as an agent for treating anyother voiding dysfunction or polyuria associated with a decreased AVPlevel, such as pollakiuria, urinary incontinence, and nocturnalenuresis.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing temporal changes in urine volumes ofindividual groups in the pharmacological test (4): antidiuresis test incontinuously hydrated rats with additional water loading. The verticalaxis represents urine volume (mL/30 min) and the horizontal axisrepresents elapsed time (hr) from the administration of the testcompound. Groups represented by “ . . . +Water” are water-loaded groups.The arrows in the horizontal axis represent the time points ofadditional water-loading.

DESCRIPTION OF EMBODIMENTS

Hereinafter, the present invention will be described in detail.

In the present specification, the “lower alkyl” is a straight orbranched alkyl having one to ten carbon atoms (hereinafter, abbreviatedas C₁₋₁₀). In one embodiment, the lower alkyl is a straight or branchedC₁₋₆ alkyl, specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, isopentyl, isohexyl, isoheptyl,isooctyl, 3-ethylpentyl, 4-ethylhexyl, 4-ethylheptyl, n-hexyl,hexan-2-yl, 4-methylpentan-2-yl, 2,2-dimethylpropyl, 3,3-dimethylpentylor 3,3-dimethylbutyl. The lower alkyl is, in one embodiment, a C₁₋₄alkyl; in one embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl or tert-butyl; and in one embodiment, methyl orethyl.

The “C₁₋₁₀ alkyl” in the definition of R¹ and R³ is a straight orbranched C₁₋₁₀ alkyl in the above defined “lower alkyl”. The “C₁₋₁₀alkyl” of R¹¹ is, in one embodiment, methyl, n-hexyl, hexan-2-yl,4-methylpentan-2-yl, 3,3-dimethylpentyl or 3,3-dimethylbutyl. The “C₁₋₁₀alkyl” of R³ is, in one embodiment, a branched C₁₋₁₀ alkyl; in oneembodiment, isobutyl, isopentyl, isohexyl, 2,2-dimethylpropyl or3-ethylpentyl; and in one embodiment, isobutyl.

The “lower alkenyl” is a straight or branched C₂₋₈ alkenyl;specifically, vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl,1-methyl-2-propenyl, 2-methyl-1-propenyl, 1,3-butadienyl,3-methyl-1,3-butadienyl or 1,3-pentadienyl; in one embodiment, a C₂₋₆alkenyl; in one embodiment, 2-methyl-1-propenyl or3-methyl-1,3-butadienyl; and in one embodiment, 2-methyl-1-propenyl.

The “lower alkynyl” is a straight or branched C₂₋₆ alkynyl;specifically, ethynyl, propynyl, butynyl, pentynyl, 1-methyl-2-propynyl,1,3-butadiynyl or 1,3-pentadiynyl; in one embodiment, a C₂₋₄ alkynyl; inone embodiment, ethynyl, 2-propynyl or 3-butynyl; and in one embodiment,3-butynyl.

The “lower alkylene” is a straight or branched C₁₋₁₀ alkylene;specifically, methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, heptamethylene, octamethylene, propylene,methylmethylene, ethylethylene, 1,2-dimethylethylene or1,1,2,2-tetramethylethylene; in one embodiment, a C₁₋₆ alkylene; in oneembodiment, a C₁₋₄ alkylene; in one embodiment, methylene, ethylene,trimethylene, propylene or methylmethylene; and in one embodiment,methylene or ethylene.

The “lower alkenylene” is a straight or branched C₂₋₆ alkenylene;specifically, vinylene, ethylidene, propenylene, butenylene,pentenylene, hexenylene, 1,3-butadienylene or 1,3-pentadienylene; in oneembodiment, a C₂₋₄ alkenylene; in one embodiment, vinylene orethylidene; and in one embodiment, vinylene.

The “lower alkynylene” is a straight or branched C₂₋₆ alkynylene;specifically, ethynylene, propynylene, butynylene, pentynylene,hexynylene, 1,3-butadiynylene or 1,3-pentadiynylene; in one embodiment,a C₂₋₄ alkynylene; and in one embodiment, ethynylene or propynylene.

The “halogen” is F, Cl, Br or I.

The “lower halogenoalkyl” is a straight or branched C₁₋₁₀ alkylsubstituted by one or more halogens. The lower halogenoalkyl is, in oneembodiment, a C₁₋₆ alkyl substituted by one to five halogens; in oneembodiment, trifluoromethyl, trifluoroethyl, trifluoropropyl,2-fluoro-2-methylpropyl, difluoromethyl, fluoromethyl or chloromethyl;and in one embodiment, trifluoromethyl.

The “C₃₋₁₂ cycloalkyl” is a C₃₋₁₂ saturated hydrocarbon ring group whichis optionally cross-linked and optionally forms a spiro ring. The C₃₋₁₂cycloalkyl is, specifically, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2,2,1]heptyl,bicyclo[3,1,0]hexyl, bicyclo[3,1,1]heptyl, adamantyl, spiro[2,5]octyl,spiro[3,5]nonyl or spiro[4,5]decyl; in one embodiment, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[2,2,1]heptyl, bicyclo[3,1,0]hexyl,bicyclo[3,1,1]heptyl, adamantyl, spiro[2,5]octyl, spiro[3,5]nonyl orspiro[4,5]decyl; and in one embodiment, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. The “C₃₋₁₀ cycloalkyl” and the “C₃₋₈cycloalkyl” is C₃₋₁₀ and C₃₋₈ saturated hydrocarbon ring groups,respectively, included in the above defined “C₃₋₁₂ cycloalkyl”.

The “C₃₋₁₂ cycloalkenyl” is a C₃₋₁₂ hydrocarbon ring group having one ormore unsaturated bonds, which is optionally cross-linked, and optionallyforms a spiro-ring. The C₃₋₁₂ cycloalkenyl is, specifically,cyclopentenyl, cyclopentadienyl, cyclohexenyl or cyclohexadienyl. The“C₅₋₁₀ cycloalkenyl” is included in the above defined “C₃₋₁₂cycloalkenyl”. In the “C₃₋₁₂ cycloalkenyl which may be condensed with abenzene ring optionally having one to four substituents selected fromthe Group G³”, the “C₃₋₁₂ cycloalkenyl condensed with a benzene ring” isa C₃₋₁₂ cycloalkenyl having a benzene ring condensed therewith on theposition of an unsaturated bond of the C₃₋₁₂ cycloalkenyl. The “C₃₋₁₂cycloalkenyl condensed with a benzene ring” is, specifically,1-tetrahydronaphthyl, 2-tetrahydronaphthyl, dihydroinden-1-yl,dihydroinden-2-yl, 1-indenyl, 2-indenyl or 9-fluorenyl. The “C₅₋₆cycloalkenyl condensed with a benzene ring” is included in the abovedefined “C₃₋₁₂ cycloalkenyl condensed with a benzene ring”; in oneembodiment, 1-tetrahydronaphthyl, 2-tetrahydronaphthyl,dihydroinden-1-yl or dihydroinden-2-yl; and in one embodiment,dihydroinden-2-yl.

The “aryl” is a C₆₋₁₄ mono-, bi- or tri-cyclic aromatic hydrocarbon ringgroup; specifically, phenyl or naphthyl; and in one embodiment, phenyl.

The “mono- or bi-cyclic heterocyclic group” is a 3- to 15-membered, inone embodiment 5- to 10-membered, mono- or bi-cyclic heterocyclic grouphaving 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,saturated, aromatic or partially hydrogenated heterocyclic group. Asulfur or nitrogen ring atom of the heterocyclic group is optionallyoxidized to form an oxide or dioxide. The mono- or bi-cyclicheterocyclic group is, specifically, monocyclic heteroaryl such aspyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl,triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl,oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl and thelike; bicyclic heteroaryl such as indolyl, isoindolyl, benzimidazolyl,indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl,phthalazinyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl,benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl and the like;saturated or partially hydrogenated monocyclic heterocyclic group, suchas azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, azepanyl,diazepanyl, morpholinyl, thiomorpholinyl, tetrahydropyridinyl,dihydropyridinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl,dioxolanyl, dioxanyl, tetrahydrothiopyranyl, dihydrothiopyranyl and thelike; saturated or partially hydrogenated bicyclic heterocyclic group,such as indolinyl, isoindolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, dihydrobenzimidazolyl, tetrahydrobenzimidazolyl,tetrahydroquinoxalinyl, dihydroquinoxalinyl, dihydrobenzoxazolyl,dihydrobenzoxadinyl, dihydrobenzofuryl, chromanyl, chromenyl,methylenedioxyphenyl, ethylenedioxyphenyl and the like; or cross-linkedheterocyclic group such as quinuclidinyl and the like. The mono- orbi-cyclic heterocyclic group is, in one embodiment, a 5- to 10-memberedmonocyclic heterocyclic group; in one embodiment, a 5- to 6-memberedmonocyclic heterocyclic group; in one embodiment, a 5- to 6-memberedmonocyclic heteroaryl; and in one embodiment, a 5- to 6-memberedsaturated or partially hydrogenated monocyclic heterocyclic group. The“mono- or bi-cyclic heterocyclic group” of R¹ is, in one embodiment,piperidyl, tetrahydropyranyl, thienyl, thiazolyl or pyrazolyl; and inone embodiment, piperidyl, tetrahydropyranyl, thienyl or pyrazolyl. The“mono- or bi-cyclic heterocyclic group” of R³ is, in one embodiment,piperidyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, pyridyl,pyrazinyl, pyrimidinyl or pyrazolyl; and in one embodiment, pyridyl,pyrazinyl, pyrimidinyl or pyrazolyl.

The “saturated monocyclic heterocyclic group” is a saturated andmonocyclic heterocyclic group in the “mono- or bi-cyclic heterocyclicgroup” defined above; specifically, azetidinyl, pyrrolidinyl, piperidyl,piperazinyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dioxolanyl,dioxanyl or tetrahydrothiopyranyl; and in one embodiment,tetrahydropyranyl. The “—CH=(saturated monocyclic heterocycle)” is agroup in which CH is bonded to one ring carbon atom of the saturatedmonocyclic heterocycle by a double bond.

In the “R⁴ forms together with neighboring —NR¹, as —NR¹R⁴, a 4- to8-membered nitrogen-containing saturated heterocyclic group, wherein thenitrogen-containing saturated heterocyclic group may be condensed with abenzene ring and optionally has one to five substituents selected fromthe Group G⁴”, the “4- to 8-membered nitrogen-containing saturatedheterocyclic group” is a 4- to 8-membered monocyclic nitrogen-containingsaturated heterocyclic group or such a heterocyclic group condensed witha benzene ring, in the “mono- or bi-cyclic heterocyclic group” definedabove; specifically, 1-azetidinyl, 1-pyrrolidinyl, piperidino,1-piperazinyl, 1-azepanyl, 1-diazepanyl, morpholino, indolin-1-yl,isoindolin-2-yl, tetrahydroquinolin-1-yl, tetrahydroisoquinolin-2-yl ortetrahydroquinoxalin-1-yl; in one embodiment, piperidino or1,2,3,4-tetrahydroisoquinolin-2-yl; and in one embodiment, piperidino.Wherein the “4- to 8-membered nitrogen-containing saturated heterocyclicgroup” optionally has one to five substituents selected from the GroupG⁴ and the substituents are bonded to one or more ring atom(s) of theheterocycle (and/or the condensed benzene ring).

The “ester group” in the definition of R^(P) is an ester group, such aslower alkyl, lower alkenyl, lower halogenoalkyl, C₃₋₈ cycloalkyl, (loweralkyl)-O-benzyl, nitrobenzyl, (lower alkyl)-O-benzhydryl, benzhydryl,-(lower alkylene)-O—C(O)-(lower alkyl), -(lower alkylene)-C(O)-(loweralkenyl), -(lower alkylene)-O—C(O)—O—(C₃₋₈ cycloalkyl), -(loweralkylene)-O—C(O)-(lower alkenyl), -(lower alkylene)-O—C(O)-(loweralkylene)-O-(lower alkyl), -(lower alkylene)-O-(lower alkyl), -(loweralkylene)-O-(lower alkylene)-O-(lower alkyl), -(loweralkylene)-O—C(O)—O-(lower alkyl), -(lower alkylene)-O—C(O)—O-(loweralkylene)-O-(lower alkyl), -(lower alkylene)-O-benzoyl, -(loweralkylene)-N(lower alkyl)₂, 2-oxotetrahydrofuran-5-yl,2-oxo-5-alkyl-1,3-dioxolen-4-ylmethyl,tetrahydrofuranylcarbonyloxymethyl, or 3-phthalidyl. In one embodiment,the ester group is a lower alkyl group. A compound in which R^(P) is anester group may be a compound which can be converted into acorresponding carboxylic acid compound under physiological conditions.The present invention also encompasses such a compound.

The “R^(P) and R⁶ are linked to each other to form, together with—O—C(═O)—C—O— to which they are attached, 2,2-di(loweralkyl)-4-oxo-1,3-dioxolane-5,5-diyl” means that the compound representedby Formula (1) includes compounds represented by Formula (I-A):

wherein, R^(P1) and R^(P2) are the same or different from each other,and are a lower alkyl. In one embodiment, both R^(P1) and R^(P2)represent methyl.

In the “—X—R¹ is optionally linked to any one of R²'s attached to apyridine ring to which —X—R¹ is also attached, to constitute a grouprepresented by any one of formulae —X^(b)—(CH₂)_(m)—Y—, —X^(b)—CH═CH—,—X^(b)—CH═N—, and —X^(b)—N═CH—, and form a heterocycle condensed withthe pyridine ring”, the “heterocycle condensed with a pyridine ring”includes condensed rings represented by Formulae (i) to (iv) below. Sucha condensed ring has a bond to —CH₂—C(OR⁶)(COOR^(P))—CH(NH₂)—R³ at anyone of carbon ring atoms neighboring the nitrogen ring atom of thepyridine ring (i.e. on the position 2 or 6 in the pyridine ring). Such aheterocycle optionally has one to five substituents selected from theGroup G⁴ in replacement of one or more H atoms attached to the ringatom(s) of the heterocycle.

wherein, X^(b) is O, S or NH; m is an integer of 1 to 3; and Y is CH₂,O, S or NH.

In one embodiment, the “heterocycle condensed with a pyridine ring” is acondensed ring selected from the group consisting of the followingrings:

Among the above condensed rings, the heterocycle condensed with apyridine ring is, in one embodiment, selected from the group consistingof the condensed rings (a), (b), (d), (e), (g), (h), (k), (m), (o), (p),(q), (r), (s), and (t); in one embodiment, selected from the groupconsisting of the condensed rings (b), (d), (o), (p), (q), and (r); inone embodiment, selected from the group consisting of the condensedrings (d) and (q); and in one embodiment, the condensed ring (q).

In one embodiment, the heterocycle condensed with a pyridine ring isselected from the group consisting of the following condensed rings:

The heterocycle condensed with a pyridine ring is, in one embodiment,the condensed ring (d-1) or (q-1) among the above condensed rings; andin one embodiment, the condensed ring (q-1).

The “—X—R¹ is optionally linked to R³ to form a group represented byformula —X—(C₅₋₁₅ carbon chain)-, wherein the C₅₋₁₅ carbon chainoptionally has one to two O or S atoms in replacement of C atom(s),optionally has one to five unsaturated bonds” means that the C₅₋₁₅carbon chain is a straight or branched alkylene having 5 to 15 carbonatoms, or a straight or branched alkenylene or alkynylene having 5 to 15carbon atoms and 1 to 5 unsaturated bonds, and that 1 to 2 carbon atomsof the carbon chain may be replaced by O or S atom(s). The —X—(C₅₋₁₅carbon chain)-is, specifically, —X—(C₅₋₁₅ alkylene)-, —X—(C₅₋₁₅alkenylene)-, —X—(C_(q1) alkylene)-O—(C_(q2) alkylene)-, —X—(C_(q1)alkylene)-S—(C_(q2) alkylene)-, —X—(C_(q1) alkenylene)-O—(C_(q2)alkylene)-, —X—(C_(q1) alkenylene)-S—(C_(q2) alkylene)-, —X—(C_(q1)alkylene)-O—(C_(q2) alkenylene)-, —X—(C_(q1) alkylene)-S—(C_(q2)alkenylene)-, —X—(C_(r), alkylene)-O—(C_(r2) alkylene)-O—(C_(r3)alkylene)-, —X—(C_(r1) alkylene)-S—(C_(r2) alkylene)-S—(C_(r3)alkylene)-, —X—(C_(r1) alkenylene)-O—(C_(r2) alkylene)-O—(C_(r3)alkylene)-, —X—(C_(r1) alkenylene)-S—(C_(r2) alkylene)-S—(C_(r3)alkylene)-, —X—(C_(r1) alkylene)-O—(C_(r2) alkenylene)-O—(C_(r3)alkylene)- or —X—(C_(r1) alkylene)-S—(C_(r2) alkenylene)-S—(C_(r3)alkylene)-. If the carbon chain is an alkylene, q1, q2, r1, r2, and r3are each an integer of one or over, and if the carbon chain is analkenylene, q1, q2, r1, r2, and r3 are each an integer of two or over,with the proviso that q1+q2=5 to 14 and r1+r2+r3=5 to 13. The —X—(C₅₋₁₅carbon chain)-is, in one embodiment, —X—(C_(q1) alkylene)-O—(C_(q2)alkylene)- or —X—(C_(q1) alkenylene)-O—(C_(q2) alkylene)-; and in oneembodiment, —X—(C₅₋₁₁ alkenylene)-O—(C₁₋₃ alkylene)- or —X—(C₅₋₁₁alkylene)-O—(C₁₋₃ alkylene)-. In one embodiment, a compound in which—X—R¹ is linked to R³ to form a group represented by formula —X—(C₅₋₁₅carbon chain)-is represented by Formula (I-B) or (I-C):

wherein, the double bond represented with two crossed lines indicatesthat the double bond forms an E isomer or Z isomer, or a mixturethereof.

The “—O—(C₂₋₃ alkylene)-O—” and the “—O—(C₃₋₄ alkylene)-” eachrepresents a bivalent substituent group having two bonds to the samering carbon atom. Specifically, “—O—(C₂₋₃ alkylene)-O—” is —O—(CH₂)₂—O—or —O—(CH₂)₃—O—, and “—O—(C₃₋₄ alkylene)-” is —O—(CH₂)₃— or —O—(CH₂)₄—.

In the present specification, the “optionally has one to fivesubstituents” means that the specified group is unsubstituted or has oneto five substituents. If the specified group has a plurality ofsubstituents, the substituents may be the same or different from eachother.

The compound represented by Formula (I) has at least two asymmetriccarbon atoms. One asymmetric carbon atom attached to —C(O)OR^(P)(position 2) has (R) configuration, and neighboring carbon atom attachedto —NH₂ (position 3) may have either (R) or (S) configuration, and thecompound represented by Formula (I) includes (R) or (S) isomer onposition 3, and a mixture thereof. In one embodiment, the compoundrepresented by Formula (1) is a compound represented by Formula (1′) ora salt thereof:

wherein, (2R) indicates that the carbon atom at position 2 has (R)configuration.

The compound represented by Formula (I) may have tautomers and geometricisomers, depending on the type of substituent groups. The compoundrepresented by Formula (1) also includes separate tautomers andgeometric isomers, and mixtures thereof.

The compound represented by Formula (I) may also have stereoisomersbased on other asymmetric carbon atom than those described above,depending on the type of substituent groups. The compound represented byFormula (I) also includes separate stereoisomers and mixtures thereof.

The present invention also encompasses a pharmaceutically acceptableprodrug of the compound represented by Formula (I). A pharmaceuticallyacceptable prodrug is a compound having a group which can be convertedinto an amino group, a hydroxyl group, or a carboxyl group as a resultof solvolysis or under physiological conditions. Examples of a groupforming a prodrug are described in Prog. Med., 5, 2157-2161 (1985),“Iyakuhin no Kaihatsu (Pharmaceutical Research and Development)”(Hirokawa-Shoten Ltd.), 1990, Vol. 7, “Bunshi Sekkei (Drug MolecularDesign)”, pp. 163-198, and “Prodrugs and targeted delivery” (Wiley-VCH2011) Methods and principles in medicinal chemistry, volume 47.

The salt of the compound represented by Formula (I) is apharmaceutically acceptable salt of the compound represented by Formula(I). The compound represented by Formula (1) may form an acid additionsalt or a salt with a base, depending on the type of substituent groups.Specific examples of the salt include acid addition salts with inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, nitric acid, and phosphoric acid; acid addition saltswith organic acids such as formic acid, acetic acid, propionic acid,oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid,lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaricacid, ditoluoyltartaric acid, citric acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,aspartic acid, and glutamic acid; salts with inorganic bases such assodium, potassium, magnesium, calcium, and aluminum; salts with organicbases such as methylamine, ethylamine, ethanolamine, lysine, andornithine; salts with various amino acids and amino acid derivativessuch as acetylleucine; and ammonium salts.

The present invention also encompasses various hydrates, solvates, andcrystalline polymorphs of the compound represented by Formula (I) and asalt thereof. The present invention also encompasses various compoundslabeled with a radioactive or nonradioactive isotope.

Some embodiments of the compound represented by Formula (I) are shownbelow.

(1-1) The compound or a salt thereof, in which X is O, S or NR⁴; R⁴ isH, lower alkyl which optionally has one to five substituents selectedfrom the Group G¹, C₃₋₁₂ cycloalkyl which optionally has one to fivesubstituents selected from the Group G², -(lower alkylene)-(C₃₋₁₂cycloalkyl which optionally has one to five substituents selected fromthe Group G²), —C(O)-(lower alkyl which optionally has one to fivesubstituents selected from the Group G¹), —C(O)—(C₃₋₁₂ cycloalkyl whichoptionally has one to five substituents selected from the Group G²), or—C(O)-(lower alkylene)-(C₃₋₁₂ cycloalkyl which optionally has one tofive substituents selected from the Group G²); or R⁴ forms together withneighboring —NR¹, as —NR¹R⁴, a 4- to 8-membered nitrogen-containingsaturated heterocyclic group, wherein the nitrogen-containing saturatedheterocyclic group may be condensed with a benzene ring and optionallyhas one to five substituents selected from the Group G⁴.

(1-2) The compound or a salt thereof, in which X is O, S or NR⁴; R⁴ isH; lower alkyl which optionally has one to five substituents selectedfrom the group consisting of halogen, OH and —O-(lower alkyl); C₃₋₁₂cycloalkyl which optionally has one to five substituents selected fromthe group consisting of lower alkyl, halogen, OH and —O-(lower alkyl);-(lower alkylene)-{C₃₋₁₂ cycloalkyl which optionally has one to fivesubstituents selected from the group consisting of lower alkyl, halogen,OH and —O-(lower alkyl)}; —C(O)-{lower alkyl which optionally has one tofive substituents selected from the group consisting of halogen, OH and—O-(lower alkyl)); —C(O)—{C₃₋₁₂ cycloalkyl which optionally has one tofive substituents selected from the group consisting of lower alkyl,halogen, OH and —O-(lower alkyl)}; or —C(O)-(lower alkylene)-{C₃₋₁₂cycloalkyl which optionally has one to five substituents selected fromthe group consisting of lower alkyl, halogen, OH and —O-(lower alkyl)};or R⁴ forms together with neighboring —NR¹, as —NR¹R⁴, a 4- to8-membered nitrogen-containing saturated heterocyclic group, wherein thenitrogen-containing saturated heterocyclic group may be condensed with abenzene ring and optionally has one to three substituents selected fromthe group consisting of lower alkyl, halogen, OH and —O-(lower alkyl).

(1-3) The compound or a salt thereof, in which X is O, S or NR⁴; R⁴ isH, lower alkyl which is optionally substituted by one to five halogens,C₃₋₁₂ cycloalkyl, or —C(O)—(C₃₋₁₂ cycloalkyl which is optionallysubstituted by one to five lower alkyls); or R⁴ forms together withneighboring —NR¹, as —NR¹R⁴, a 4- to 8-membered nitrogen-containingsaturated heterocyclic group, wherein the nitrogen-containing saturatedheterocyclic group may be condensed with a benzene ring and isoptionally substituted by one to five lower alkyls.

(1-4) The compound or a salt thereof, in which X is O or S.

(1-5) The compound or a salt thereof, in which X is NR⁴; R⁴ is H, loweralkyl which is optionally substituted by one to five halogens, C₃₋₁₂cycloalkyl, or —C(O)—(C₃₋₁₂ cycloalkyl which is optionally substitutedby one to five lower alkyls); or R⁴ forms together with neighboring—NR¹, as —NR¹R⁴, a 4- to 8-membered nitrogen-containing saturatedheterocyclic group, wherein the nitrogen-containing saturatedheterocyclic group may be condensed with a benzene ring and isoptionally substituted by one to five lower alkyls.

(1-6) The compound or a salt thereof, in which X is O.

(1-7) The compound or a salt thereof, in which X is S.

(2-1) The compound or a salt thereof, in which:

(a) R¹ is H, C₁₋₁₀ alkyl which optionally has one to five substituentsselected from the Group G¹, -(lower alkylene)-X¹¹-(lower alkyl whichoptionally has one to five substituents selected from the Group G¹),R¹¹, -(lower alkylene)-R¹, -(lower alkylene)-X¹¹—R¹¹, or -(loweralkylene)-X¹¹-(lower alkylene)-R¹¹; R¹¹ is C₃₋₁₂ cycloalkyl whichoptionally has one to five substituents selected from the Group G²,C₃₋₁₂ cycloalkenyl which optionally has one to five substituentsselected from the Group G² and which may be condensed with a benzenering optionally having one to four substituents selected from the GroupG³, aryl which optionally has one to five substituents selected from theGroup G⁵, or mono- or bi-cyclic heterocyclic group which optionally hasone to five substituents selected from the Group G⁵; X¹¹ is O orS(O)_(n), wherein n is 0, 1, or 2;(b) R³ is C₁₋₁₀ alkyl which is optionally substituted by one to fivehalogens; —X—R¹ is linked to any one of R²'s attached to a pyridine ringto which —X—R¹ is also attached, to constitute a group represented byany one of formulae —X^(b)—(CH₂)_(m)—Y—, —X^(b)—CH═CH—, —X^(b)—CH═N—,and —X^(b)—N═CH—, and form a heterocycle condensed with the pyridinering, wherein m is an integer of 1 to 3, X^(b) is O, S or NH, Y is CH₂,O, S or NH, and the heterocycle optionally has one to four substituentsselected from the group consisting of: C₃₋₁₂ cycloalkyl which optionallyhas one to five substituents selected from the Group G²; -(loweralkylene)-(C₃₋₁₂ cycloalkyl which optionally has one to fivesubstituents selected from the Group G²); and the substituents definedin the Group G³; in replacement of one or more H atoms attached to thering atom(s) of the heterocycle; or(c) —X—R¹ is linked to R³ to form a group represented by formula—X—(C₅₋₁₅ carbon chain)-, wherein the C₅₋₁₅ carbon chain optionally hasone to two O or S atoms in replacement of C atom(s), optionally has oneto five unsaturated bonds, and optionally has one to five substituentsselected from the Group G⁴.

(2-1a) The compound or a salt thereof according to (a) in (2-1).

(2-2) The compound or a salt thereof, in which:

(a) R¹ is H; C₁₋₁₀ alkyl which optionally has one to five substituentsselected from the group consisting of halogen and OH; -(loweralkylene)-X¹¹-{lower alkyl which optionally has one to five substituentsselected from the group consisting of halogen, OH, —O-(lower alkyl) and—O-(lower halogenoalkyl)}; C₃₋₁₂ cycloalkyl which optionally has one tofive substituents selected from the group consisting of lower alkyl,halogen, lower halogenoalkyl, OH, —O-(lower alkyl), —O-(lowerhalogenoalkyl), —O—(C₂₋₃ alkylene)-O— and —O—(C₃₋₄ alkylene)-; C₃₋₁₂cycloalkenyl which optionally has one to five substituents selected fromthe group consisting of lower alkyl, halogen, lower halogenoalkyl, OH,—O-(lower alkyl) and —O-(lower halogenoalkyl), and which may becondensed with a benzene ring; aryl which optionally has one to fivesubstituents selected from the group consisting of lower alkyl, halogen,lower halogenoalkyl, OH, —O-(lower alkyl) and —O-(lower halogenoalkyl);mono- or bi-cyclic heterocyclic group which optionally has one to fivesubstituents selected from the group consisting of lower alkyl, halogen,lower halogenoalkyl, OH, —O-(lower alkyl), —O-(lower halogenoalkyl),—C(O)-(lower alkyl) and —C(O)—O-(lower alkylene)-aryl; -(loweralkylene)-R¹¹; -(lower alkylene)-X¹¹—R¹¹; or -(loweralkylene)-X¹¹-(lower alkylene)-R¹¹; R¹¹ is C₃₋₁₂ cycloalkyl whichoptionally has one to five substituents selected from the groupconsisting of lower alkyl, halogen, lower halogenoalkyl, OH, —O-(loweralkyl), —O-(lower halogenoalkyl), —O—(C₂₋₃ alkylene)-O— and —O—(C₃₋₄alkylene)-; C₃₋₁₂ cycloalkenyl which optionally has one to fivesubstituents selected from the group consisting of lower alkyl, halogen,lower halogenoalkyl, OH, —O-(lower alkyl) and —O-(lower halogenoalkyl),and which may be condensed with a benzene ring; aryl which optionallyhas one to five substituents selected from the group consisting of loweralkyl, halogen, lower halogenoalkyl, OH, —O-(lower alkyl) and —O-(lowerhalogenoalkyl); or mono- or bi-cyclic heterocyclic group whichoptionally has one to five substituents selected from the groupconsisting of lower alkyl, halogen, lower halogenoalkyl, OH, —O-(loweralkyl) and —O-(lower halogenoalkyl); X¹¹ is O or S;(b) R³ is C₁₋₁₀ alkyl which is optionally substituted by one to fivehalogens; —X—R¹ is linked to any one of R²'s attached to a pyridine ringto which —X—R¹ is also attached, to constitute a group represented byany one of formulae —X^(b)—(CH₂)_(m)—Y—, —X^(b)—CH═CH—, —X^(b)—CH═N—,and —X^(b)—N═CH—, and form a heterocycle condensed with the pyridinering, wherein m is an integer of 1 to 2, X^(b) is O, S or NH, Y is CH₂,O, S or NH, and the heterocycle optionally has one to four substituentsselected from the group consisting of: C₃₋₁₂ cycloalkyl which optionallyhas one to five substituents selected from the group consisting of loweralkyl, halogen, lower halogenoalkyl, OH, —O-(lower alkyl), —O-(lowerhalogenoalkyl), —O—(C₂₋₃ alkylene)-O— and —O—(C₃₋₄ alkylene)-; -(loweralkylene)-{C₃₋₁₂ cycloalkyl which optionally has one to fivesubstituents selected from the group consisting of lower alkyl, halogen,lower halogenoalkyl, OH, —O-(lower alkyl), —O-(lower halogenoalkyl),—O—(C₂₋₃ alkylene)-O— and —O—(C₃₋₄ alkylene)-}; lower alkyl; halogen;lower halogenoalkyl; OH; —O-(lower alkyl); —O-(lower alkylene)-aryl;—O-aryl; —S-(lower alkyl); and —O-lower halogenoalkyl; in replacement ofone or more H atoms attached to the ring atom(s) of the heterocycle; or(c) —X—R¹ is linked to R³ to form —X—(C₅₋₁₁ alkylene)-O—(C₁₋₃ alkylene)-or —X—(C₅₋₁₁ alkenylene)-O—(C₁₋₃ alkylene)-.

(2-2a) The compound or a salt thereof according to (a) in (2-2).

(2-3) The compound or a salt thereof, in which:

(a) R¹ is H; C₁₋₁₀ alkyl; -(lower alkylene)-O-(lower alkyl); C₃₋₁₂cycloalkyl which optionally has one to five substituents selected fromthe group consisting of lower alkyl, halogen and —O—(C₃₋₄ alkylene)-;C₅₋₆ cycloalkenyl condensed with a benzene ring; aryl which optionallyhas one to five substituents selected from the group consisting ofhalogen and —O-(lower alkyl); 5- to 6-membered monocyclic heterocyclicgroup which optionally has one to five substituents selected from thegroup consisting of lower alkyl, —C(O)-(lower alkyl) and —C(O)—O-(loweralkylene)-aryl; -(lower alkylene)-R¹¹; -(lower alkylene)-O—(C₃₋₁₂cycloalkyl); -(lower alkylene)-O-aryl; or -(lower alkylene)-O-(loweralkylene)-aryl; R¹¹ is C₃₋₁₂ cycloalkyl which is optionally substitutedby one to five lower alkyls; aryl which optionally has one to fivesubstituents selected from the group consisting of halogen, lowerhalogenoalkyl, —O-(lower alkyl) and —O-(lower halogenoalkyl); or 5- to6-membered monocyclic heterocyclic group which is optionally substitutedby one to five lower alkyls;(b) R³ is C₁₋₁₀ alkyl which is optionally substituted by one to fivehalogens; —X—R¹ is linked to any one of R²'s attached to a pyridine ringto which —X—R¹ is also attached, to constitute a group represented byany one of formulae —O—CH₂—CH₂—O—, —O—CH₂—CH₂—, —NH—CH═CH—, —NH—CH═N—,—O—CH═CH— and —S—CH═CH—, and form a heterocycle condensed with thepyridine ring, wherein the heterocycle condensed with the pyridine ringis selected from the group consisting of rings represented by Formulae(b-1), (d-1), (o-1), (p-1), (q-1), and (r-1):

wherein the heterocycle has one to two substituents selected from thegroup consisting of -(lower alkylene)-(C₃₋₁₂ cycloalkyl) and loweralkyl, in replacement of one or more H atoms attached to the ringatom(s) of the heterocycle; and the other R² is 11; or (c) a compoundrepresented by Formula (I-B 1) or (I-C1) or a salt thereof:

in which the double bond represented with two crossed lines indicatesthat the double bond forms an E isomer, Z isomer or mixture thereof.

(2-4) The compound or a salt thereof according to (a) or (b) in (2-3).

(2-5) The compound or a salt thereof according to (a) in (2-3).

(2-6) The compound or a salt thereof according to (b) in (2-3).

(2-7) The compound or a salt thereof, in which R¹ is C₁₋₁₀ alkyl, C₃₋₁₀cycloalkyl which is optionally substituted by one to three lower alkyls,-(lower alkylene)-(C₃₋₁₀ cycloalkyl which is optionally substituted byone to three lower alkyls), or -(lower alkylene)-aryl.

(2-8) The compound or a salt thereof, in which R¹ is C₁₋₁₀ alkyl, C₃₋₁₀cycloalkyl which is optionally substituted by lower alkyl, or -(loweralkylene)-(C₃₋₁₀ cycloalkyl which is optionally substituted by loweralkyl).

(2-9) The compound or a salt thereof, in which R¹ is hexan-2-yl,4-methylcyclohexyl, cyclohexyl, cycloheptyl, spiro[2,5]octyl,2-(cyclopropyl)ethyl, 2-(1-methylcyclopropyl)ethyl or3-(cyclopropyl)propyl.

(2-10) The compound or a salt thereof, in which R¹ is C₁₋₁₀ alkyl.

(2-11) The compound or a salt thereof, in which R¹ is C₃₋₁₀ cycloalkylwhich is optionally substituted by one to three lower alkyls.

(2-12) The compound or a salt thereof, in which R¹ is cyclohexyl,cycloheptyl, 4-methylcyclohexyl or spiro[2,5]octyl.

(2-13) The compound or a salt thereof, in which R¹ is -(loweralkylene)-(C₃₋₁₀ cycloalkyl which is optionally substituted by one tothree lower alkyls).

(2-14) The compound or a salt thereof, in which R¹ is2-(cyclopropyl)ethyl, 2-(1-methylcyclopropyl)ethyl or3-(cyclopropyl)propyl.

(2-15) The compound or a salt thereof according to (2-6), wherein —X—R¹is linked to any one of R²'s attached to a pyridine ring to which —X—R¹is also attached, to constitute a group represented by any one offormulae —O—CH₂—CH₂— and —O—CH—CH—, and form a heterocycle condensedwith the pyridine ring as represented by Formula (d-1) or (q-1), and theheterocycle has -(lower alkylene)-(C₃₋₁₀ cycloalkyl) in replacement ofone H atom attached to a ring atom of the heterocycle.

(2-16) The compound or a salt thereof according to (2-15), wherein —X—R¹is linked to any one of R²'s attached to a pyridine ring to which —X—R¹is also attached, to constitute a group represented by formula—O—CH═CH—, and form a heterocycle condensed with the pyridine ring asrepresented by Formula (q-1), and the heterocycle has -(loweralkylene)-(C₃₋₁₀ cycloalkyl) in replacement of one H atom attached to aring atom of the heterocycle.

(3-1) The compound or a salt thereof, in which R²'s are the same ordifferent from each other, and are H, lower alkyl which optionally hasone to five substituents selected from the Group G¹, halogen, OH, SH,—O-(lower alkyl), —O-(lower alkylene)-aryl, —O-aryl, —S-(lower alkyl),—S-(lower alkylene)-aryl, —S-aryl, —O-(lower halogenoalkyl),—C(O)-(lower alkyl), —S(O)₂-(lower alkyl), —S(O)-(lower alkyl), NO₂,—NH₂, —NH-(lower alkyl), —N(lower alkyl)₂, —NH-aryl, —N(loweralkyl)-aryl, —C(O)OH, —C(O)O-(lower alkyl), —CHO, —C(O)NH₂,—C(O)NH-(lower alkyl), —C(O)N(lower alkyl)₂, CN, -(loweralkylene)-X²¹-(lower alkyl which optionally has one to five substituentsselected from the Group G¹), C₃₋₁₂ cycloalkyl which optionally has oneto five substituents selected from the Group G², C₃₋₁₂ cycloalkenylwhich optionally has one to five substituents selected from the Group G²and which may be condensed with a benzene ring optionally having one tofour substituents selected from the Group G³, aryl which optionally hasone to five substituents selected from the Group G⁵, -(loweralkylene)-R²¹, -(lower alkylene)-X²¹—R²¹, or -(loweralkylene)-X²¹-(lower alkylene)-R²¹;

R²¹ is C₃₋₁₂ cycloalkyl which optionally has one to five substituentsselected from the Group G², C₃₋₁₂ cycloalkenyl which optionally has oneto five substituents selected from the Group G² and which may becondensed with a benzene ring optionally having one to four substituentsselected from the Group G³, aryl which optionally has one to fivesubstituents selected from the Group G⁵, or mono- or bi-cyclicheterocyclic group which optionally has one to five substituentsselected from the Group G⁵; and X²¹ is O or S(O)_(n), wherein n is 0, 1,or 2.

(3-2) The compound or a salt thereof, in which R²'s are the same ordifferent from each other, and are H, lower alkyl, lower halogenoalkyl,halogen, OH, —O-(lower alkyl), —O-(lower alkylene)-aryl, —O-aryl,—S-(lower alkyl), —O-(lower halogenoalkyl), -(lower alkylene)-O-(loweralkyl), C₃₋₁₂ cycloalkyl which optionally has one to five substituentsselected from the group consisting of lower alkyl, lower halogenoalkyland halogen, -(lower alkylene)-(C₃₋₁₂ cycloalkyl which optionally hasone to five substituents selected from the group consisting of loweralkyl, lower halogenoalkyl and halogen), -(lower alkylene)-O—(C₃₋₁₂cycloalkyl which optionally has one to five substituents selected fromthe group consisting of lower alkyl, lower halogenoalkyl and halogen),-(lower alkylene)-O-(lower alkylene)-(C₃₋₁₂ cycloalkyl which optionallyhas one to five substituents selected from the group consisting of loweralkyl, lower halogenoalkyl and halogen), -(lower alkylene)-(aryl whichoptionally has one to five substituents selected from the groupconsisting of lower alkyl, lower halogenoalkyl and halogen), -(loweralkylene)-O-(aryl which optionally has one to five substituents selectedfrom the group consisting of lower alkyl, lower halogenoalkyl andhalogen), or -(lower alkylene)-O-(lower alkylene)-(aryl which optionallyhas one to five substituents selected from the group consisting of loweralkyl, lower halogenoalkyl and halogen).

(3-3) The compound or a salt thereof, in which R²'s are the same ordifferent from each other, and are H, lower alkyl, halogen, -(loweralkylene)-aryl or -(lower alkylene)-O-(lower alkylene)-aryl.

(3-4) The compound or a salt thereof, in which R²'s are the same ordifferent from each other, and are H or lower alkyl.

(3-5) The compound or a salt thereof, in which R²'s are H.

(4-1) The compound or a salt thereof, in which R³ is R³², -(loweralkylene)-X¹¹—R³², -(lower alkenylene)-X—R³², R³¹, -(lower alkylene)-R¹,-(lower alkylene)-X³¹—R³¹, -(lower alkylene)-X³¹-(lower alkylene)-R³¹,-(lower alkenylene)-R³¹, -(lower alkynylene)-R^(3′) or —CH=(saturatedmonocyclic heterocycle); R³¹ is C₃₋₁₂ cycloalkyl which optionally hasone to five substituents selected from the Group G², C₃₋₁₂ cycloalkenylwhich optionally has one to five substituents selected from the Group G²and which may be condensed with a benzene ring optionally having one tofour substituents selected from the Group G³, aryl which optionally hasone to five substituents selected from the Group G⁵, or mono- orbi-cyclic heterocyclic group which optionally has one to fivesubstituents selected from the Group G⁵; and X³¹ is O or S(O)_(n),wherein n is 0, 1, or 2.

(4-2) The compound or a salt thereof, in which R³ is C₁₋₁₀ alkyl whichoptionally has one to five substituents selected from the groupconsisting of halogen and OH, lower alkenyl which optionally has one tofive substituents selected from the group consisting of halogen and OH,lower alkynyl which optionally has one to five substituents selectedfrom the group consisting of halogen and OH, -(loweralkylene)-X³¹-{lower alkyl which optionally has one to five substituentsselected from the group consisting of halogen, OH, —O-(lower alkyl) and—O-(lower halogenoalkyl)}, -(lower alkylene)-X³¹-{lower alkenyl whichoptionally has one to five substituents selected from the groupconsisting of halogen, OH, —O-(lower alkyl) and —O-(lowerhalogenoalkyl)), -(lower alkylene)-O-{lower alkynyl which optionally hasone to five substituents selected from the group consisting of halogen,OH, —O-(lower alkyl) and —O-(lower halogenoalkyl)}, -(loweralkenylene)-O-{lower alkenyl which optionally has one to fivesubstituents selected from the group consisting of halogen, OH,—O-(lower alkyl) and —O-(lower halogenoalkyl)}, -(loweralkenylene)-O-{lower alkyl which optionally has one to five substituentsselected from the group consisting of halogen, OH, —O-(lower alkyl) and—O-(lower halogenoalkyl)}, R³¹, -(lower alkylene)-R³¹, -(loweralkylene)-X³¹—R³¹, -(lower alkylene)-X³¹-(lower alkylene)-R³¹, -(loweralkenylene)-R³¹, or —CH=(saturated monocyclic heterocycle);

R³¹ is C₃₋₁₂ cycloalkyl which optionally has one to five substituentsselected from the Group G², C₃₋₁₂ cycloalkenyl which optionally has oneto five substituents selected from the Group G² and which may becondensed with a benzene ring optionally having one to four substituentsselected from the Group G³, aryl which optionally has one to fivesubstituents selected from the Group G⁵, or mono- or bi-cyclicheterocyclic group which optionally has one to five substituentsselected from the Group G⁵;

X³¹ is O or S(O), wherein n is 0, 1, or 2;

Group G² consists of lower alkyl, halogen, lower halogenoalkyl, OH,—O-(lower alkyl) and —O-(lower halogenoalkyl);

Group G⁵ consists of: i) halogen, OH, SH, —O-(lower alkyl), —O-(loweralkylene)-aryl, —O-aryl, —S-(lower alkyl), —O-(lower halogenoalkyl),—C(O)-(lower alkyl), —S(O)₂-(lower alkyl) and CN; ii) lower alkyl, lowerhalogenoalklyl, lower alkenyl, and lower alkynyl; iii) -(loweralkylene)-O-(lower alkyl), -(lower alkylene)-O-(lower halogenoalkyl),and -(lower alkylene)-O-(lower alkyl substituted by one or more hydroxygroups); iv) C₃₋₁₂ cycloalkyl which optionally has one to fivesubstituents selected from the Group G², and C₃₋₁₂ cycloalkenyl whichmay be condensed with a benzene ring; v) aryl which optionally has oneto five substituents selected from the Group G³; vi) mono- or bi-cyclicheterocyclic group which optionally has one to five substituentsselected from the Group G³; vii) -(lower alkylene)-R^(G); viii) -(loweralkylene)-O—R^(G); ix) —C(O)—R^(G); and x) —S(O)₂—R^(G), wherein R^(G)'sare the same or different from each other, and are C₃₋₁₂ cycloalkylwhich optionally has one to five substituents selected from the GroupG², C₃₋₁₂ cycloalkenyl which optionally has one to five substituentsselected from the Group G² and may be condensed with a benzene ringoptionally having one to four substituents selected from the Group G³,aryl which optionally has one to five substituents selected from theGroup G³, or a mono- or bi-cyclic heterocyclic group which optionallyhas one to five substituents selected from the Group G³; and

Group G³ consists of lower alkyl, halogen, lower halogenoalkyl, OH,—O-(lower alkyl), —O-(lower halogenoalkyl), —C(O)-(lower alkyl) and—S(O)₂-(lower alkyl).

(4-3) The compound or a salt thereof, in which R³ is: C₁₋₁₀ alkyl whichis optionally substituted by one to five halogens; -(loweralkylene)-O-(lower alkyl which optionally has one to five substituentsselected from the group consisting of halogen and OH); -(loweralkylene)-O-(lower alkenyl); aryl which optionally has one to fivesubstituents selected from the group consisting of halogen, CN, -(loweralkylene)-O-(lower alkyl), C₃₋₈ cycloalkyl, aryl which is optionallysubstituted by —S(O)₂-(lower alkyl), 5- to 6-membered monocyclicheterocyclic group, and —S(O)₂—(C₃₋₈ cycloalkyl); -(loweralkylene)-(C₃₋₈ cycloalkyl); -(lower alkylene)-(5- to 6-memberedmonocyclic heterocyclic group); -(lower alkylene)-O—(C₃₋₈ cycloalkyl);-(lower alkylene)-O-(aryl which optionally has one to five substituentsselected from the group consisting of halogen, —O-(lower alkyl), CN, and-(lower alkylene)-O-(lower alkyl)}; -(lower alkylene)-O-(5- to6-membered monocyclic heterocyclic group which optionally has one tofive substituents selected from the group consisting of halogen, loweralkyl and lower halogenoalkyl); -(lower alkylene)-O-(loweralkylene)-aryl; -(lower alkylene)-O-(lower alkylene)-(C₃₋₈ cycloalkyl);-(lower alkylene)-S(O)_(n)-(lower alkyl), wherein n is 0, 1, or 2;-(lower alkylene)-S—(C₃₋₈ cycloalkyl); -(lower alkylene)-S-(loweralkylene)-(C₃₋₈ cycloalkyl); -(lower alkenylene)-aryl; or —CH=(saturatedmonocyclic heterocycle).

(4-4) The compound or a salt thereof, in which R³ is: C₁₋₁₀ alkyl whichis optionally substituted by one to five halogens; -(loweralkylene)-O-(lower alkyl which optionally has one to five substituentsselected from the group consisting of halogen and OH); -(loweralkylene)-O-(lower alkenyl); -(lower alkylene)-(C₃₋₈ cycloalkyl);-(lower alkylene)-O—(C₃₋₈ cycloalkyl); -(lower alkylene)-O-(loweralkylene)-(C₃₋₈ cycloalkyl); -(lower alkylene)-S-(lower alkyl); -(loweralkylene)-S—(C₃₋₈ cycloalkyl); -(lower alkylene)-S-(loweralkylene)-(C₃₋₈ cycloalkyl); -(lower alkylene)-O-{aryl which optionallyhas one to five substituents selected from the group consisting ofhalogen, —O-(lower alkyl), CN and -(lower alkylene)-O-(lower alkyl)}; or-(lower alkylene)-O-(5- to 6-membered monocyclic heterocyclic groupwhich optionally has one to five substituents selected from the groupconsisting of halogen, lower alkyl and lower halogenoalkyl).

(4-5) The compound or a salt thereof, in which R³ is C₁₋₁₀ alkyl,-(lower alkylene)-O-(lower alkenyl), -(lower alkylene)-(C₃₋₈cycloalkyl), -(lower alkylene)-O-(lower alkylene)-(C₃₋₈ cycloalkyl),-(lower alkylene)-S-(lower alkyl), -(lower alkylene)-S-(loweralkylene)-(C₃₋₈ cycloalkyl), or -(lower alkylene)-O-(pyridyl optionallysubstituted by one to five halogens).

(4-6) The compound or a salt thereof, in which R³ is C₁₋₁₀ alkyl,-(lower alkylene)-(C₃₋₈ cycloalkyl), -(lower alkylene)-S-(lower alkyl),or -(lower alkylene)-S-(lower alkylene)-(C₃₋₈ cycloalkyl).

(4-7) The compound or a salt thereof, in which R³ is isobutyl,isopentyl, 2,2-dimethylpropyl, 2-fluoro-2-methylpropyl,3,3,3-trifluoropropyl, 2-(cyclopropyl)ethyl, 2-(cyclobutyl)ethyl,2-(cyclopentyl)ethyl, 3-(cyclopropyl)propyl,2-(cyclopropyl)ethyloxymethyl, methylthiomethyl, ethylthiomethyl,n-propylthiomethyl, isopropylthiomethyl, isobutylthiomethyl,cyclobutylthiomethyl, cyclopropylmethylthiom ethyl,cyclobutylmethylthiomethyl, or 2-(cyclopropyl)ethylthiomethyl.

(4-8) The compound or a salt thereof, in which R³ is C₁₋₁₀ alkyl,-(lower alkylene)-(C₃₋₈ cycloalkyl), or -(lower alkylene)-S-(loweralkylene)-(C₃₋₈ cycloalkyl).

(4-9) The compound or a salt thereof, in which R³ is isobutyl,2-(cyclobutyl)ethyl, or cyclopropylmethylthiomethyl.

(4-10) The compound or a salt thereof, in which R³ is C₁₋₁₀ alkyloptionally substituted by one to five halogens.

(4-11) The compound or a salt thereof, in which R³ is C₁₋₁₀ alkyl.

(4-12) The compound or a salt thereof, in which R³ is isobutyl.

(4-13) The compound or a salt thereof, in which R³ is -(loweralkylene)-(C₃₋₈ cycloalkyl).

(4-14) The compound or a salt thereof, in which R³ is -(loweralkylene)-S-(lower alkylene)-(C₃₋₈ cycloalkyl).

(4-15) The compound or a salt thereof, in which R³ iscyclopropylmethylthiomethyl.

(4-16) The compound or a salt thereof, in which R³ is -(loweralkylene)-S-(lower alkyl).

(4-17) The compound or a salt thereof, in which R³ is methylthiomethylor ethylthiomethyl.

(5-1) The compound or a salt thereof, in which R^(P) is H or an estergroup and R⁶ is H; or R^(P) and R¹¹ are linked to each other to form,together with —O—C(═O)—C—O— to which they are attached, 2,2-di(loweralkyl)-4-oxo-1,3-dioxolane-5,5-diyl.

(5-2) The compound or a salt thereof, in which R^(P) is H, or an estergroup selected from the group consisting of: lower alkyl, lower alkenyl,lower halogenoalkyl, C₃₋₈ cycloalkyl, (lower alkyl)-O-benzyl,nitrobenzyl, (lower alkyl)-O-benzhydryl, benzhydryl, -(loweralkylene)-O—C(O)-(lower alkyl), -(lower alkylene)-C(O)-(lower alkenyl),-(lower alkylene)-O—C(O)—O—(C₃₋₈ cycloalkyl), -(loweralkylene)-O—C(O)-(lower alkenyl), -(lower alkylene)-O—C(O)-(loweralkylene)-O-(lower alkyl), -(lower alkylene)-O-(lower alkyl), -(loweralkylene)-O-(lower alkylene)-O-(lower alkyl), -(loweralkylene)-O—C(O)—O-(lower alkyl), -(lower alkylene)-O—C(O)—O-(loweralkylene)-O-(lower alkyl), -(lower alkylene)-O-benzoyl, -(loweralkylene)-N(lower alkyl)₂, 2-oxotetrahydrofuran-5-yl,2-oxo-5-alkyl-1,3-dioxolen-4-ylmethyl,tetrahydrofuranylcarbonyloxymethyl and 3-phthalidyl, and R⁶ is H; orR^(P) and R⁶ are linked to each other to form, together with—O—C(═O)—C—O— to which they are attached, 2,2-di(loweralkyl)-4-oxo-1,3-dioxolane-5,5-diyl.

(5-3) The compound or a salt thereof, in which R^(P) is H or loweralkyl, and R⁶ is H; or R^(P) and R⁶ are linked to each other to form,together with —O—C(═O)—C—O— to which they are attached,2,2-dimethyl-4-oxo-1,3-dioxolane-5,5-diyl.

(5-4) The compound or a salt thereof, in which R^(P) is H or an estergroup set forth in (5-2), and R⁶ is H.

(5-5) The compound or a salt thereof, in which R^(P) is H or loweralkyl, and R⁶ is H.

(5-6) The compound or a salt thereof, in which R^(P) is H and R⁶ is H.

(6) The compound or a salt thereof, according to a combination of anyone of the embodiments (1-1) to (1-7), any one of the embodiments (2-1)to (2-16), any one of the embodiments (3-1) to (3-5), any one of theembodiments (4-1) to (4-17), and any one of the embodiments (5-1) to(5-6). Specific examples thereof include the following embodiments, butare not limited to:

(6-1) The compound or a salt thereof, according to a combination of theembodiments (1-2), (2-2), (3-2), (4-2), and (5-2).

(6-1a) The compound or a salt thereof, according to a combination of theembodiments (1-2), (2-2a), (3-2), (4-2), and (5-2).

(6-2) The compound or a salt thereof, according to a combination of theembodiments (1-3), (2-3), (3-3), (4-3), and (5-3).

(6-2a) The compound or a salt thereof, according to a combination of theembodiments (1-3), (2-5), (3-3), (4-3), and (5-3).

(6-3) The compound or a salt thereof, according to a combination of theembodiments (1-4), (2-4), (3-4), (4-4), and (5-5).

(6-4) The compound or a salt thereof, which is a combination of theembodiments (1-4), (2-2a), (3-4), (4-2), and (5-6).

(6-5) The compound or a salt thereof, which is a combination of theembodiments (2-6) and (5-6).

(6-6) The compound or a salt thereof, according to a combination of theembodiments (1-4), (2-7), (3-5), (4-5), and (5-6).

(6-7) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-8), (3-5), (4-6), and (5-6).

(6-8) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-9), (3-5), (4-7), and (5-6).

(6-9) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-8), (3-5), (4-8), and (5-6).

(6-10) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-9), (3-5), (4-9), and (5-6).

(6-11) The compound or a salt thereof, according to a combination of theembodiments (2-15), (4-11), and (5-6).

(6-12) The compound or a salt thereof, according to a combination of theembodiments (1-7), (2-7), (3-5), (4-5), and (5-6).

(6-13) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-5), (3-2), (4-2), and (5-5).

(6-14) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-11), (3-2), (4-2), and (5-5).

(6-15) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-13), (3-2), (4-2), and (5-5).

(6-16) The compound or a salt thereof, according to a combination of theembodiments (1-4), (2-5), (3-2), (4-10), and (5-5).

(6-17) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-10), (3-5), (4-11), and (5-6).

(6-18) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-11), (3-5), (4-11), and (5-6).

(6-19) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-11), (3-5), (4-14), and (5-6).

(6-20) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-13), (3-5), (4-11), and (5-6).

(6-21) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-13), (3-5), (4-13), and (5-6).

(6-22) The compound or a salt thereof, according to a combination of theembodiments (2-16), (4-11), and (5-6).

(6-23) The compound or a salt thereof, according to a combination of theembodiments (1-6), (2-11), (3-5), (4-16), and (5-6).

In one embodiment, the compound represented by Formula (1) is a compoundrepresented by Formula (r) according to any one of the embodiments (6-1)to (6-23).

In one embodiment, the compound represented by Formula (I) or a saltthereof is a compound selected from the group consisting of thefollowing compounds, or a salt thereof:

-   (2R,3S)-3-amino-2-{[4-(2-cyclopropyl    ethoxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoic acid;-   (2R,3S)-3-amino-2-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoic    acid;-   (2R,3S)-3-amino-2-hydroxy-5-methyl-2-{[4-(spiro[2.5]oct-6-yloxy)pyridin-2-yl]methyl}hexanoic    acid;-   (2R,3R)-3-amino-4-[(cyclopropylmethyl)sulfanyl]-2-hydroxy-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)butanoic    acid;-   (2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoic    acid;-   (2R,3S)-3-amino-5-cyclobutyl-2-{[4-(2-cyclopropylethoxy)pyridin-2-yl]methyl}-2-hydroxypentanoic    acid;-   (2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[2-(1-methylcyclopropyl)ethoxy]pyridin-2-yl)}methyl)hexanoic    acid;-   (2R,3S)-3-amino-2-{[4-(3-cyclopropylpropoxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoic    acid;-   (2R,3S)-3-amino-2-{[4-(cycloheptyl    oxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoic acid; and-   (2R,3S)-3-amino-2-({4-[(2R)-hexan-2-yloxy]pyridin-2-yl}methyl)-2-hydroxy-5-methylhexanoic    acid.

The compound represented by Formula (I) or a salt thereof is, in oneembodiment, a compound selected from the group consisting of thecompounds described above and the following compounds, or a saltthereof:

-   (2R,3R)-3-amino-4-(ethylsulfanyl)-2-hydroxy-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)butanoic    acid; and-   (2R,3R)-3-amino-2-hydroxy-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-(methyl    sulfanyl)butanoic acid.

In other embodiments, the compound represented by Formula (I) or a saltthereof is (2R,3S)-3-amino-2-([2-(2-cyclopropylethyl)furo[3,2-c]pyridin-4-yl]methyl}-2-hydroxy-5-methylhexanoic acid ora salt thereof.

(Preparation Methods)

The compound represented by the formula (I) or a salt thereof can beprepared using the characteristics based on the basic structure or thetype of substituents and by applying various known synthesis methods.During the preparation, replacement of the functional group with asuitable protective group (a group that can be easily converted into thefunctional group) at the stage from starting material to an intermediatemay be effective depending on the type of functional groups in theproduction technology in some cases. Such a protective group mayinclude, for example, the protective groups described in “Greene'sProtective Groups in Organic Synthesis (4th edition, 2006)”, P. G. M.Wuts and T. W. Greene, and one of these may be selected and used asnecessary depending on the reaction conditions. In this kind of method,a desired compound can be obtained by introducing the protective group,by carrying out the reaction and by eliminating the protective group asnecessary.

Hereinbelow, the representative preparation methods for the compoundrepresented by the formula (I) will be described. Each of the productionprocesses may also be carried out with reference to the Referencesappended in the present description. Further, the preparation methods ofthe present invention are not limited to the examples as shown below.

(Production Process 1)

In the formula, P^(O) represents a protective group for a hydroxylgroup, and P^(N) represents a protective group for an amino group.

The compound (I-D) can be produced by ring-opening and deprotection ofthe compound (II).

In this reaction, the compound (II) and a hydrolytic reagent inequivalent amounts, or either thereof in an excess amount, are used, andthe mixture is stirred for usually 0.1 hour to five days in a solventwhich is inert to the reaction under from cooling to heating withreflux. Examples of the solvent used herein are not particularlylimited, but include alcohols such as methanol, ethanol and propanol;halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane andchloroform; 1,4-dioxane; N,N-dimethylformamide; tetrahydrofuran and thelike. In some cases, a mixed solvent of such a solvent and water ispreferably used for the reaction. Examples of the hydrolytic reagentused herein are not particularly limited, but include bases such asaqueous sodium hydroxide solution and aqueous potassium hydroxidesolution; and acids such as hydrochloric acid and trifluoroacetic acid.In some cases, it is preferred to treat the compound (II) with a baseand then with an acid, or to treat it with an acid and then with a base.

Examples of P^(O), the protective group for a hydroxyl group, includemethoxymethyl, benzyloxymethyl and the like. Examples of P^(N), theprotective group for an amino group, include methoxymethyl,benzyloxymethyl and the like.

(Production Process 2)

The compound (I-E) can be prepared by deprotection of the compound(III).

In this reaction, the compound (III) and a deprotecting reagent inequivalent amounts, or either thereof in an excess amount, are used, andthe mixture is stirred for usually 0.1 hour to five days in a solventwhich is inert to the reaction or in the absence of a solvent, underfrom cooling to heating with reflux. Examples of the solvent used hereinare not particularly limited, but include alcohols such as methanol,ethanol and propanol; halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane and chloroform; 1,4-dioxane; N,N-dimethylformamide;tetrahydrofuran and the like. In some cases, a mixed solvent of such asolvent and water is preferably used for the reaction. Examples of thedeprotecting reagent are not particularly limited, but include basessuch as aqueous sodium hydroxide solution and aqueous potassiumhydroxide solution; and acids such as hydrochloric acid andtrifluoroacetic acid. In some cases, it is preferred to treat thecompound (III) with a base and then with an acid, or to treat it with anacid and then with a base.

Examples of P^(N), the protective group for an amino group, includetert-butoxycarbonyl, methoxymethyl, benzyloxymethyl and the like.

The compound (I-A) can also be prepared from the compound (III) underselected reaction conditions. For example, the compound (I-A) can beprepared by using tert-butoxycarbonyl as the protective group P^(N) andtreating with hydrogen chloride, trifluoroacetic acid and the like, in asolvent such as 1,4-dioxane or toluene.

(Production Process 3)

In the formula, L represents a leaving group.

The compound (I-D) can be prepared by reacting the compound (IV) withthe compound (V). Examples of the leaving group L include halogen,methanesulfonyloxy, trifluoromethanesulfonyloxy and p-toluenesulfonyloxygroups.

In this reaction, the compounds (IV) and (V) in equivalent amounts, oreither thereof in an excess amount, are used, the mixture is stirred forusually 0.1 hour to five days in a solvent which is inert to thereaction in the presence of a base under from cooling to heating withreflux, preferably at a temperature of 0 to 180° C. The reaction may becarried out under microwave irradiation. Examples of the solvent usedherein are not particularly limited, but include aromatic hydrocarbonssuch as benzene, toluene and xylene; ethers such as diethylether,tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; halogenatedhydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform;N,N-dimethylformamide; dimethylsulfoxide; ethyl acetate; acetonitrile;and a mixture thereof. Examples of the base include organic bases suchas triethylamine, diisopropylethylamine, potassium hexamethyldisilazide,1,8-diazabicyclo[5.4.0]-undec-7-ene, n-butyllithium and potassiumtert-butoxide; and inorganic bases such as sodium carbonate, potassiumcarbonate, cesium carbonate and sodium hydride. In some cases, thereaction is advantageously carried out in the presence of a phasetransfer catalyst, such as tetra-n-butylammonium chloride.

REFERENCES

-   “Organic Functional Group Preparations” written by S. R. Sandler    and W. Karo, 2nd edition, Vol. 1, Academic Press Inc., 1991-   “Courses in Experimental Chemistry (5th edition)” edited by The    Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

(Other Production Process)

A compound of Formula (I) prepared by the respective productionprocesses can be used as a starting material and is subjected to achemical modification reaction generally used by those skilled in theart, such as cyanation, hydrogenation and esterification, to produceother compounds represented by Formula (I).

(Synthesis of Starting Material 1)

The compound (II-A) can be prepared by Mitsunobu reaction of thecompounds (1) and (2).

In this reaction, the compounds (1) and (2) in equivalent amounts, oreither thereof in an excess amount, are used, the mixture of thecompounds and a Tsunoda reagent is stirred for usually 0.1 hour to fivedays in a solvent which is inert to the reaction under from cooling toheating with reflux, preferably at a temperature of 0 to 180° C. Thereaction may be carried out under microwave irradiation. In some cases,the reaction may be preferably carried out under argon or nitrogenatmosphere and/or under anhydrous conditions. Examples of the Tsunodareagent used herein include (cyanomethylene)tri-n-butylphosphorane(CMBP) and (cyanomethylene)trimethylphosphorane (CMMP). Examples of thesolvent used herein are not particularly limited, but include aromatichydrocarbons such as benzene, toluene and xylene, and a mixture thereof.

REFERENCES

-   Tetsuto Tsunoda and Sho Ito, Journal of Synthetic Organic Chemistry,    Japan, 1997, 55(7), 631-641-   T. Tsunoda et al, Tetrahedron letters, 1996, 37(14), 2459-2462

(Synthesis of Starting Material 2)

The compound (II) can be prepared by reacting the compound (3) with thecompound (V).

This reaction can be carried out by the same method as in the ProductionProcess 3 described above.

(Synthesis of Starting Material 3)

(Step 1)

The compound (5) can be prepared through introduction of protectivegroups in the compound (4). The P^(O) and P^(N) may be the same, and arespecifically methoxymethyl or benzyloxymethyl.

(Step 2)

The compound (7) can be prepared through iodination of the compound (6)by Finkelstein reaction.

REFERENCE

-   Chirality, 2011, 23(1), 24-33

(Step 3)

The compound (8) can be prepared by reacting the compound (5) with thecompound (7).

In this reaction, the compounds (5) and (7) in equivalent amounts, oreither thereof in an excess amount, are used, the mixture is stirred forusually 0.1 hour to five days in a solvent which is inert to thereaction in the presence of a base under from cooling to heating,preferably under cooling. Examples of the solvent used herein are notparticularly limited, but include aromatic hydrocarbons such as benzene,toluene and xylene; ethers such as diethylether, tetrahydrofuran,1,4-dioxane and 1,2-dimethoxyethane; hexane; and a mixture thereof.Examples of the base include organic bases such as lithiumdiisopropylamide, triethylamine, diisopropylethylamine, potassiumhexamethyldisilazide, 1,8-diazabicyclo[5.4.0]-undec-7-ene andn-butyllithium; and inorganic bases such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydride and potassium tert-butoxide.

REFERENCES

-   Journal of Organic Chemistry, 1990, 55(20), 5525-5528-   Tetrahedron Letters, 2000, 41(33), 6523-6526

(Step 4)

The compound (1) can be prepared by catalytic hydrogenation reaction ofthe compound (8).

In this reaction, the compound (8) is stirred for one hour to five daysin a solvent which is inert to the reaction, such as methanol, ethanoland the like, in the presence of a metal catalyst under hydrogenatmosphere and under from cooling to heating, preferably at a roomtemperature. Preferred examples of the metal catalyst include palladiumcatalysts such as palladium on carbon and palladium black; platinumcatalysts such as platinum plate and platinum oxide; and nickelcatalysts such as reduced nickel and Raney nickel.

REFERENCES

-   “Organic Functional Group Preparations” written by S. R. Sandler    and W. Karo, 2nd edition, Vol. 1, Academic Press Inc., 1991-   “Courses in Experimental Chemistry (5th edition)” edited by The    Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

(Synthesis of Starting Material 4)

(Step 1)

The compound (11) can be prepared by reacting the compound (9) with thecompound (10) in the presence of pyridinium p-toluenesulfonate. In thisreaction, a mixture of the compounds (9) and (10) is stirred for onehour to five days in a solvent which is inert to the reaction in thepresence of pyridinium p-toluenesulfonate under from cooling to heating,preferably at a temperature of from 40 to 120° C. Examples of thesolvent include aromatic hydrocarbons such as benzene, toluene andxylene; ethers such as diethylether, tetrahydrofuran, 1,4-dioxane and1,2-dimethoxyethane; and halogenated hydrocarbons such asdichloromethane, 1,2-dichloroethane and chloroform.

Examples of P^(N), the protective group for an amino group, includetert-butoxycarbonyl, methoxymethyl, benzyloxymethyl and the like.

(Step 2)

In this step, the compounds (11) and (13) are prepared by reacting thecompound (11) with the compound (12). In this reaction, the compound(11) is treated with lithium diisopropylamide under argon atmosphere.The compound (12) is brominated with PBr₃ and is then added to thetreated compound (11) to cause a reaction. In this reaction, a mixtureof the compounds is stirred for one hour to five days in a solvent whichis inert to a reaction under from cooling to heating, preferably undercooling. Examples of the solvent include aromatic hydrocarbons such asbenzene, toluene and xylene; ethers such as diethylether,tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; and halogenatedhydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform.

A compound (III) having a desired configuration can be produced from astarting compound (9) in which the asymmetric carbon attached to—NHP^(N) has a specific configuration. In some cases, it is preferred toadd trimethylchlorosilane at the time of reaction of the compounds (11)and (12), depending on the configuration of the asymmetric carbonattached to —NHP^(N).

REFERENCES

-   Molecules, 2004, 9(5), 365-372-   Tetrahedron Asymmetry, 1991, 2(7), 705-720

(Synthesis of the Starting Material 5)

The compound (3) can be prepared by reacting the compound (14) with thecompound (15). The reaction can be carried out by the same method as inthe step 3 of the synthesis of the starting material 3. The compound (3)is subjected to ring-opening and deprotection to produce the compound(IV). The reaction can be carried out by the same method as in theproduction process 1.

(Synthesis of Other Starting Materials)

A desired starting compound can be produced using any other method knownto those skilled in the art. For example, the methods shown in thereaction scheme below can be used to produce the compounds (5-A), (5-B),(1-A), (3-A), (II-D) and (II-E):

wherein R³⁶ is R³², R³¹ or -(lower alkylene) R³¹; and R³⁷ is lower alkylwhich optionally has one to five substituents selected from the GroupG¹, -(lower alkylene)-X³¹-(lower alkyl which optionally has one to fivesubstituents selected from the Group G¹), R³¹, -(lower alkylene)-R³¹,-(lower alkylene)-X³¹—R³¹, or -(lower alkylene)-X¹-(lower alkylene)-R³¹.

The compounds represented by Formula (I) are isolated and purified asfree compounds, or salts, hydrates, solvates or crystalline polymorphsthereof. Salts of the compound represented by Formula (I) can also beproduced by a conventional salt forming reaction.

Isolation and purification is carried out by a general chemicalprocedure such as extraction, fractional crystallization, and varioustypes of fractional chromatography.

Various isomers can be produced by selection of appropriate startingcompounds, or can be separated based on differences in physicochemicalproperties among the isomers. For example, optical isomers can beprepared by a general optical resolution technique of racemic products(for example, fractional crystallization that converts the compound intodiastereomer salts with optically active bases or acids, orchromatography using a chiral column), or can also be produced fromappropriate optically active starting compounds.

Pharmacological effects of the compounds represented by Formula (I) wereconfirmed by the tests described below. Doses of individual testcompounds described herein are indicated as corresponding weights offree compounds.

(1) Inhibition of IRAP Activity

Rat epididymal fat pads were homogenized and subjected toultracentrifugation at 100,000×g for 30 minutes to obtain microsomescontaining IRAP. The microsomes (with a total protein content of 55μg/well) were mixed with a solvent (dimethyl sulfoxide; hereinafter,abbreviated as DMSO (final concentration: 0.1%)) or with each testcompound (common ratio: 3; maximum concentration: 10 μM). AVP was thenadded to the solution to a final concentration of 25 μM, and theresulting solution was allowed to react for one hour at 37° C. Anaqueous trifluoroacetic acid (hereinafter, abbreviated as TFA) solutionwas then added to the solution (final concentration: 1%) to stop theenzymatic reaction. Residual AVP was then determined by massspectrometry (MALDI-MS). Based on the results, ICso values (nM), i.e.concentrations required for 50% inhibition of decrease in AVP level inthe solvent control group, of the individual test compounds werecalculated by the logistic regression to evaluate inhibition of IRAPactivity. As comparative examples, similar tests were performed with thecompounds of the Reference Examples 1 and 2 described below:(2S,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoicacid dihydrochloride; and(2S,3R)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoicacid hydrochloride, respectively.

The results are shown in Tables 1 and 2, and indicate that the examplecompounds effectively inhibit AVP degradation by TRAP, i.e. a rathomolog of human P-LAP. The compounds of the Reference Examples 1 and 2have (2S) configuration, i.e. (S) configuration in position 2, while thecompounds represented by Formula (1) have (2R) configuration, i.e. (R)configuration in position 2. The results indicate that the compounds ofReference Examples 1 and 2 have less effect of inhibiting AVPdegradation by IRAP in comparison with the example compounds, andsuggest that the configuration in position 2 influences on the effect ofinhibiting AVP degradation.

(2) Inhibition of Human P-LAP (hP-LAP) Activity

HEK293 cells forced to transiently express hP-LAP (J Biol Chem 1996;271: 56-61) were prepared by lipofection, homogenized, and thensubjected to ultracentrifugation at 100,000×g for 30 minutes. Microsomescontaining hP-LAP were thereby prepared. The microsomes (with a totalprotein content of 0.5 to 1.5 μg/well) were mixed with a solvent (DMSO;final concentration: 0.1%) or with each test compound (common ratio: 3;maximum concentration: 10 μM). AVP was then added to the solution into afinal concentration of 25 μM, and the resulting solution was allowed toreact for one hour at 37° C. An aqueous TFA solution was then added tothe solution (final concentration: 1%) to stop the enzymatic reaction.Residual AVP was then determined by mass spectrometry (MALDI-MS). Basedon the results, IC₅₀ values (nM), i.e. concentrations required for 50%inhibition of decrease in AVP level in the solvent control group, of theindividual test compounds were calculated by logistic regression toevaluate inhibition of human P-LAP (hP-LAP) activity. The results areshown in Tables 1 and 2 and indicate that the example compoundseffectively inhibit AVP degradation by hP-LAP.

In the Tables 1 and 2 below, numerals in the column “Ex” indicateExample numbers related to the respective test compounds; “−” indicatesan unadministered test; “S-1” indicates the compound of ReferenceExample 1; and “S-2” indicates the compound of Reference Example 2. Thevalue with the symbol “*” represents a value measured using adihydrochloride salt of the compound of the Example.

TABLE 1 IRAP hP-LAP Ex IC₅₀ (nM) IC₅₀ (nM)  1 1.5 3.2   2(1) 1.8 4.6  2(2) 6.0 6.8  3 1.6 2.5  4 1.7 2.4  5 2.3 7.2  6 1.2 1.3   7(1) 8.94.5   7(2) 200 —  8 170 —  9 1.7 8.5 10 4.9 16   11 23 52   12 30 21  13 1.3 1.0 14 1.5 3.1 15 11 7.2 16 8.6 14     17(2) 11 8.6 18 11 5.6 1920 34   20 2.4 10   21 4.0 11   22 250 — 23 8.2 13   24 6.2 4.0 25 2.71.8 26 5.2 1.9 27 9.5 8.9 28 1.2 2.9 29 2.2 4.1 30 11 2.7 31 27 20   32120 200    33 2.5 1.5 34 48 33   35 10 15   36 4.9 2.6 37 2.9 7.8 38 4.110   39 33 17   40 8.0 3.0 41 1.8 4.2 42 3.8 3.8 43 1.9 2.8 44 1.9 1.845 0.42  0.89 46 12 4.0 47 2.0 1.5 48 5.2 1.6 49 4.1 2.9 50 14 13   5113 16   52 8.8 4.0 53 290 — 54 10 10   55 1.9 2.1 56 1.8 2.0 57 130 — 581.3 3.0 59 1.7 4.4 60 2.0 1.6 61 1.9 1.8 62 290 — 63 34 63   64 7.6 4.665 39 22   66 1.9 2.3 67 1.9 1.8 68 5.4* 22*   69 7.3 8.6 70 13 17   7115 45   72 0.77  0.94 73 1.1 1.6 74 5.3 9.8 75 1.2 2.3 76 4.9 17   778.8 2.6 78 6.7 4.0 79 33 30   80 6.4 6.5 81 6.5 3.8 82 1.9 3.6 83 4.324   84 2.7 3.7 85 110 — 86 6.6 5.9 87 1.4 1.3 88 2.4 12   89 12 9.0 901.0  0.95 91 15 16   92 1.1 1.2 93 4.1 5.2 94 6.8 9.1 95 1.5 1.5 96 8.76.9 97 2.8 3.0 98 4.9 3.2 99 7.4 43   100  2.0 3.0 101  200 — 102  6.57.2

TABLE 2 IRAP hP-LAP IRAP hP-LAP IRAP hP-LAP Ex IC₅₀(nM) IC₅₀(nM) ExIC₅₀(nM) IC₅₀(nM) Ex IC₅₀(nM) IC₅₀(nM) 103 1.0 1.4 118 35 120 133 1.07.1 104 21 26 119 3.3 13 134 19 27 105 0.62 1.9 120 3.7 9.7 135 15 31106 2.5 8.7 121 1.6 13 136 4.8 5.5 107 1.7 4.5 122 4.8 26 137 3.8 13 1082.1 4.5 123 6.1 35 138 14 18 109 35 74 124 0.92 2.9 139 8.5 15 110 9.846 125 0.90 5.2 140 3.0 14 111 3.2 17 126 1.5 4.2 141 2.0 21 112 26 49127 2.0 10 142 2.6 21 113 12 32 128 6.5 6.0 143 1.9 13 114 13 84 129 5598 144 2.9 21 115 8.1 38 130 3.3 51 145 0.77 1.3 116 4.0 21 131 0.91 4.9146 19 24 117 15 7.9 132 1.8 5.2 S-1 2,400 — S-2 5,200 —

(3) Antidiuresis Test in Water-Loaded Rats (Oral Administration)

Individual test compounds were dissolved in a vehicle (containing 10%N,N-dimethylformamide, 10% propylene glycol, and 80% distilled water),and the resulting solution was orally administered to the rats. Rats ina vehicle control group were administered only with the vehicle. Onehour after the administration, 30 ml/kg of distilled water was orallyadministered to the rats. One hour after the water loading, the urinevolume was measured (urine volumes less than 0.3 ml were considered as 0ml) to calculate the ratio of the urine volume (urinary excretion rate)to the amount of water load.

The inhibition of urination (%) in the compound-administered group incomparison with the vehicle control group was calculated in accordancewith the following expression (each group consisted of four to fiverats):

Inhibition of urination (%)={[(urinary excretion rate in the vehiclecontrol group)−(urinary excretion rate in the compound-administeredgroup]/(urinary excretion rate in the vehicle control group)}×100

Table 3 shows inhibition of urination (%) observed when some examplecompounds included in compounds of Formula (I) were respectivelyadministered in the amount of 3 mg/kg. The value with a symbol “*”represents inhibition (%) observed when 1 mg/kg of the correspondingcompound was administered.

TABLE 3 Ex Inhibition (%) 1 88 3 59 4 93 5 90 6 96 9 82 18 52 20 94 2892 29 93 41 55 55 91 83 80 84 64 88 89 92 61 103  92* 105 98 110 57 11157 119 97 139 90 143 100 

The results shown above suggest that the compounds represented byFormula (I) inhibit P-LAP (IRAP), i.e. an aminopeptidase that cleavesAVP, to inhibit degradation of endogenous AVP, which results in areduced urine production.

(4) Antidiuresis Test in Continuously Hydrated Rats with AdditionalWater Loading (Oral Administration)

Male Wistar rats were used in the test. Initially, water load with 15mL/kg of distilled water was forcedly administered to the rats. Every 30minutes after loading water, urine volume collected during 30 minuteswas measured and distilled water was forcedly administered to the ratsin an amount equal to the urine volume excreted during the last 30minutes. This water load procedure was repeated to the termination ofthe test to maintain the diuretic state. After the urine volume every 30minutes became stable, individual example compounds included incompounds of Formula (1) (EX-a: 100 mg/kg of the compound of Example17(1); or EX-b: 30 mg/kg of the compound of Example 105) or dDAVP (30μg/kg) dissolved in a vehicle (containing 10% N,N-dimethylformamide, 10%propylene glycol, and 80% distilled water; 3 mL/kg) or in distilledwater was orally administered. The individual groups were furtherdivided into two subgroups, and additional distilled water of 15 mL/kgload was forcedly administered to one of the subgroups two times, i.e.at two hours and three hours after the administration. For comparison,the Vehicle group administered only with the vehicle was also subjectedto the additional administrations of water load. Blood was collectedfrom a half of the rats in each group subjected to additionaladministrations of water load, at three hours after the administration(immediately before the second additional water load) and from the otherhalf at four hours after the administration, and plasma sodium levelswere measured with an automatic electrolyte analyzer to determine theplasma sodium levels at three hours and four hours after theadministration, respectively (each group consisted of seven to eightrats). Changes in the urine volume in individual groups are shown inFIG. 1, and the plasma sodium levels of the group administered withadditional water loads are shown in Table 4.

TABLE 4 3 hours after administration 4 hours after administrationVehicle group 140.6 ± 0.4 mmol/L 139.6 ± 0.2 mmol/L EX-a group 134.9 ±0.4 mmol/L 133.2 ± 0.7 mmol/L EX-b group 140.4 ± 0.4 mmol/L 139.2 ± 0.5mmol/L dDAVP group 132.0 ± 0.4 mmol/L 128.0 ± 0.3 mmol/L

In EX-a, EX-b, and dDAVP groups without additional water loads, urineproduction was rapidly reduced after administration of the test compoundand was almost stopped after two hours of the administration, and suchan effect was maintained until four hours after the administration. Incontrast, in the EX-a and EX-b groups with additional water loads, urineproduction was reduced as a result of administration of the individualtest compounds but was resumed after administration of the additionalwater loads. After four hours of the administration of the testmaterial, urine volumes were recovered up to an approximately halfamount of that of the Vehicle group, while urine production was notresumed in the groups administered with dDAVP even after administrationof the additional water loads (see FIG. 1).

In the Vehicle, EX-a and EX-b groups, the plasma sodium levels slightlydecreased after three hours and four hours of the administration, whilemore significant decreases in the plasma sodium level were observed inthe dDAVP group in comparison with the Vehicle, EX-a and EX-b groups. Itis assumed that such a result reflects the decreased plasma sodium leveldue to the body fluid retention caused by the additional water loads(see Table 4).

The plasma AVP level is strictly regulated by plasma osmolality. It isknown that an excessive water intake reduces AVP production andsecretion to cause diuresis. The results indicate that the examplecompounds have an antidiuretic effect based on P-LAP inhibition byendogenous AVP and suggest that such compounds have a low impact on aplasma sodium level, even in a case of an excessive water intake,because decreased endogenous AVP level reduces the antidiuretic effect.Therefore, the compound represented by Formula (I) is expected toinvolve lower risks of hyponatremia, unlike V2 receptor agonists.

A pharmaceutical composition containing one or more compoundsrepresented by Formula (I) or salts thereof as an active ingredient canbe prepared by a common method using an excipient generally used in theart, that is, an excipient or a carrier for a pharmaceutical.

Such a pharmaceutical composition can be administered in any form, suchas oral administration of tablets, pills, capsules, granules, powder, orliquid, and parental administration by intraarticular, intravenous, orintramuscular injection, suppositories, transdermal liquid, transdermalpatches, transmucosal liquid, transmucosal patches, or inhalations.

A solid composition for oral administration may be in a form of, forexample, a tablet, powder, and granules. Such a solid compositioncontains one or more active ingredients mixed with at least one inactiveexcipient. The composition may contain an inactive additive, forexample, a lubricant, a disintegrating agent, a stabilizing agent, and asolubilizing agent, in accordance with conventional techniques. Tabletsor pills may be coated with sugar or a film of gastric or entericsoluble material, if necessary.

A liquid composition for oral administration includes a pharmaceuticallyacceptable emulsion, solution, suspension, syrup, and elixir, andcontains a common inactive diluent, for example, purified water orethanol. The liquid composition may contain an additive such as asolubilizing agent, a moisturizer, and a suspending agent; a sweeteningagent; a flavoring agent; an aromatic agent; and a preservative, inaddition to the inactive diluent.

An injection for parenteral administration contains aqueous ornon-aqueous sterile solvent, suspension, or emulsion. Examples of theaqueous solvent include distilled water for injection and physiologicalsaline. Examples of the non-aqueous solvent include alcohols such asethanol. The composition may further contain a tonicity agent, apreservative, a moisturizer, an emulsifier, a dispersant, a stabilizer,or a solubilizing agent. These components are sterilized by filtrationthrough a bacteria retentive filter, blending a bactericide, orirradiation, for example. These components may also be formulated into asterile solid composition to be dissolved or suspended in a sterilesolvent for injection before use.

If the compound represented by Formula (I) is orally administered, anappropriate daily dose is approximately 0.001 to 100 mg/kg, preferably0.1 to 30 mg/kg, more preferably 0.1 to 10 mg/kg, per body weight, andis administered daily in a single dose or in two to four separate doses.If the compound is intravenously administered, an appropriate daily doseis approximately 0.0001 to 10 mg/kg per body weight, and is administereddaily in a single dose or in separate doses. If the compound istransmucosally administered, an appropriate daily dose is approximately0.001 to 100 mg/kg per body weight, and is administered daily in asingle dose or in separate doses. The dose is appropriately determineddepending on, for example, the symptom, age, and sex of individualpatient. If the compound represented by Formula (1) is used forprevention or treatment of nocturia, it may be preferably administeredonce daily after supper or before going to bed, for example.

The pharmaceutical composition of the present invention contains one ormore compounds represented by Formula (I) or salts thereof in an amountof 0.01 to 100% by weight, in one embodiment 0.01 to 50% by weight, asan active ingredient, while the amount may vary depending on a route ofadministration, dosage form, site of administration, and the type ofexcipient or additive.

The compound represented by Formula (I) may be used in combination withvarious therapeutic agents or preventive agents for diseases to whichthe compound of Formula (I) is assumed to be effective. The compoundrepresented by Formula (I) and the agent to be used in combinationtherewith may be administered simultaneously, sequentially or at desiredtime intervals. The preparation to be simultaneously administered may becombined with the compound of Formula (1) or formulated as a separatepreparation.

EXAMPLES

Hereinbelow, the production processes for the compound represented byFormula (1) will be described in more details with reference toExamples. The present invention is not limited to the compoundsdescribed in the Examples. Production processes for starting compoundswill be described in Production Examples and production processes forcomparative compounds will be described in Reference Examples. Theproduction process for the compound represented by Formula (I) shouldnot be limited to the processes described in the specific Examplesbelow, but the compound represented by Formula (I) can be prepared by acombination of such production processes or by any method obvious tothose skilled in the art.

As used herein, the unit “mol/L” for a concentration is abbreviated as“M” for expediency. For example, “1 M aqueous sodium hydroxide solution”refers to 1 mol/L aqueous sodium hydroxide solution.

In the Examples, Production Examples and Tables below, the followingabbreviations may be used:

DMF: N,N-dimethylformamide; AcOEt: ethyl acetate; AcOH: acetic acid;THF: tetrahydrofuran; MeCN: acetonitrile; EtOH: ethanol; MeOH: methanol;DOX: 1,4-dioxane; DMSO: dimethylsulfoxide; Et₃N: triethylamine; DIPEA:diisopropylethylamine; Pd(OAc)₂: palladium acetate; Pd/C: palladium oncarbon; NaBH₄: sodium borohydride; LDA: lithium diisopropylamide; CMBP:(cyanomethylene)tri-n-butylphosphorane; CMMP: (cyanomethylene)trimethylphosphorane; ODS: octadecylsilyl; PEx: Production Example number; Ex:Example number; REx: Reference Example number; PSyn: the ProductionExample number in which a compound is prepared by the same method; Syn:Example number in which a compound is prepared by the same method; Str:chemical structural formula (Me: methyl, Et: ethyl, cHex: cyclohexyl,Boc: tert-butoxycarbonyl, Ph: phenyl, Bn: benzyl, tBu: tert-butyl, TIPS:triisopropylsilyl, TBDMS: tert-butyl(dimethyl)silyl); DATA:physicochemical data, ESI+: m/z value in mass spectrometry (electrosprayionization (ESI); representing [M+H]⁺ unless otherwise specified);APCI/ESI+: APCI/ESI-MS (atmospheric-pressure chemical ionization (APCT);APCT/EST indicates simultaneous measurement by APCI and ESI;representing [M+H]⁺ unless otherwise specified); EI: m/z value in massspectrometry (electron ionization (EI); representing [M]⁺ unlessotherwise specified); and CI+: m/z value in mass spectrometry (chemicalionization (CI); representing [M+H]⁺ unless otherwise specified).

The symbol “*” in a chemical structural formula indicates that thecorresponding compound is a single isomer having the indicatedconfiguration. The symbol “#” indicates that the corresponding compoundhas the indicated steric configuration and is a mixture of isomers whichhave (R) and (S) configurations, respectively, in an asymmetric carbonwith the steric configuration not indicated. The symbol “#2” indicatesthat the corresponding compound has the indicated configuration and is amixture of isomers which have (R) and (S) configurations, respectively,in the sulfoxide moiety. The symbol “$” indicates that the correspondingcompound has the indicated configuration and is a mixture ofexo-diastereomers in the bicyclo[2.2.1]hept-2-yl moiety. “HCl” in astructural formula indicates that the compound is a monohydrochloride,“2HCl” indicates that the compound is a dihydrochloride, and “3HCl”indicates that the compound is a trihydrochloride. A double bondrepresented with two crossed lines in a chemical formula indicates thatthe double bond forms an E isomer or Z isomer, or a mixture thereof.

In the present specification, a nomenclature software such as ACD/Name(registered trademark, Advanced Chemistry Development, Inc.) may be usedfor nomenclature of compounds in some cases.

RINT-TTRII was used in the measurement of powder X-ray diffractiondescribed herein. The diffractometry was carried out under the followingconditions: X-ray tube: Cu; tube current: 300 mA; tube voltage: 50 kV;sampling width: 0.020°; scanning speed: 4°/min; wavelength: 1.54056 Å;range of diffraction angle in measurement (20): 2.5 to 40°. In powderX-ray diffraction, the crystal lattice distance and the entire patternare important for the identification of crystals in view of thecharacteristics of the data. A diffraction angle and intensity mayslightly vary depending on the direction of crystal growth, the particlesize, and the measuring conditions, and should not be interpretedstrictly. As used herein, the diffraction angle (20) in the powder X-raydiffraction pattern is interpreted with a margin of error generallyacceptable in the measurement, for example, a margin of error of ±0.20°.

Example 1

Under argon atmosphere, CMBP (0.353 ml) was added to a mixture of(3R,4S)-3-[(4-hydroxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(150 mg), 2-cyclopropylethanol (116 mg) and toluene (1.5 ml) and themixture was stirred at 150° C. for 1 hour under microwave irradiation.The resulting reaction mixture was allowed to cool to room temperatureand subsequently purified by silica gel column chromatography(hexane/AcOEt). 6 M Aqueous sodium hydroxide solution (1.5 ml) was addedto a mixture of the obtained compound and MeOH (1.5 ml) and the mixturewas stirred at 50° C. for 2 hours. The resulting reaction mixture wasallowed to cool to room temperature and subsequently concentrated underreduced pressure. A mixture of the resulting residue and DOX (1.5 ml)was cooled with an ice-water bath, subsequently 9 M hydrochloric acid(1.5 ml) was added thereto and the mixture was stirred at 50° C. for 1hour. The resulting reaction mixture was allowed to cool to roomtemperature and subsequently concentrated under reduced pressure. Theresulting residue was purified by ODS column chromatography (MeCN/0.1%aqueous formic acid solution). After adding MeOH and MeCN to theobtained compound, the solvent was distilled off from the obtainedmixture to give(2R,3S)-3-amino-2-([4-(2-cyclopropylethoxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoicacid (27 mg) as a solid.

Example 2

6 M Hydrochloric acid (1.1 ml) was added to a mixture of(3R,4S)-3-{[4-(2-cyclopropylethoxy)pyridin-2-yl]methyl}-4-[(3-cyclopropylpropoxy)methyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(121 mg) and THF (5 ml) and the mixture was stirred at 60° C. for 1hour. The resulting reaction mixture was allowed to cool to roomtemperature and subsequently concentrated under reduced pressure. Theresulting residue was purified by ODS column chromatography (MeCN/0.1%aqueous formic acid solution) to give (1)(2R,3S)-3-amino-4-[(4-chlorohexyl)oxy]-2-{[4-(2-cyclopropylethoxy)pyridin-2-yl]methyl}-2-hydroxybutanoic acid (26.8 mg) and (2)(2R,3S)-3-amino-2-{[4-(2-cyclopropylethoxy)pyridin-2-yl]methyl}-2-hydroxy-4-[(4-hydroxyhexyl)oxy]butanoicacid (31.7 mg) each as a solid.

Example 3

6 M Aqueous sodium hydroxide solution (1.2 ml) was added to a mixture of(3R,4S)-3-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(85 mg) and MeOH (1.2 ml) and the mixture was stirred at 70° C. for 4.5hours. After cooling the resulting reaction mixture with an ice-waterbath, concentrated hydrochloric acid (1 ml) was added thereto. Theresulting reaction mixture was stirred at room temperature for 13 hoursand subsequently at 50° C. for 1.5 hours. The resulting reaction mixturewas concentrated under reduced pressure, and the residue was purified byODS column chromatography (MeCN/0.1% aqueous formic acid solution). Theobtained compound was dissolved in a mixture of MeCN and an excessamount of 1 M hydrochloric acid, the solvent was distilled off underreduced pressure to give(2R,3S)-3-amino-2-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoicacid dihydrochloride (54.6 mg) as a solid.

Example 4

6 M Aqueous sodium hydroxide solution (0.5 ml) was added to a mixture of(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-3-{[4-(spiro[2.5]octa-6-yloxy)pyridin-2-yl]methyl}azetidin-2-one(40 mg) and MeOH (0.5 ml) and the mixture was stirred at 70° C. for 5hours. After cooling the resulting reaction mixture with an ice-waterbath, 6 M hydrochloric acid (0.5 ml) was added thereto and concentratedunder reduced pressure. 1 M Hydrochloric acid (1 ml) and MeCN (0.5 ml)were added to the resulting residue and the mixture was stirred at roomtemperature for 16 hours. The obtained mixture was purified by ODScolumn chromatography (MeCN/0.1% aqueous formic acid solution) to give(2R,3S)-3-amino-2-hydroxy-5-methyl-2-{[4-(spiro[2.5]octa-6-yloxy)pyridin-2-yl]methyl}hexanoicacid (8.2 mg) as a solid.

Example 5

Trifluoroacetic acid (0.5 ml) was added to a mixture of (3R,4R)-4-{[(cyclopropylmethyl)sulfanyl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(39.7 mg) and CH₂Cl₂ (0.5 ml) and the mixture was stirred at roomtemperature overnight. The resulting reaction mixture was concentratedunder reduced pressure, MeOH (1.5 ml) and 6 M aqueous sodium hydroxidesolution (1.5 ml) were added to the residue and the mixture was stirredat room temperature overnight. 1 M Hydrochloric acid was added to theresulting reaction mixture to adjust pH to about 7 and the mixture wasconcentrated under reduced pressure. The resulting residue was purifiedby ODS column chromatography (MeCN/0.1% aqueous formic acid solution) togive(2R,3R)-3-amino-4-[(cyclopropylmethyl)sulfanyl]-2-hydroxy-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)butanoicacid (18.4 mg) as a solid.

Example 6

6 M Hydrochloric acid (1 ml) was added to(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(30 mg) and the mixture was stirred at 60° C. for 3 hours. The resultingreaction mixture was concentrated under reduced pressure, and theresidue was purified by ODS column chromatography (MeCN/0.1% aqueousformic acid solution). An excess amount of 1 M hydrochloric acid wasadded to the obtained compound and the solvent was distilled off underreduced pressure to give(2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoicacid dihydrochloride (25 mg) as a solid.

Example 7

6 M Aqueous sodium hydroxide solution (2 ml) was added to a mixture of(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-3-{[4-(1-phenylethoxy)pyridin-2-yl]methyl}azetidin-2-one(93 mg) and MeOH (4 ml) and the mixture was stirred at 60° C. for 6hours. The resulting reaction mixture was concentrated under reducedpressure. DOX (4 ml) and 1 M hydrochloric acid (20 ml) were added to theresulting residue and the mixture was stirred at room temperatureovernight. The resulting reaction mixture was concentrated under reducedpressure and the residue was purified by ODS column chromatography(MeCN/0.1% aqueous formic acid solution) to give (1)(2R,3S)-3-amino-2-hydroxy-5-methyl-2-{[4-(1-phenylethoxy)pyridin-2-yl]methyl}hexanoicacid (20.4 mg) and (2) (2R,3S)-3-amino-2-hydroxy-2-[(4-hydroxypyridin-2-yl)methyl]-5-methylhexanoicacid (13.3 mg) each as a solid.

Example 8

Hydrogen chloride (4 M DOX solution, 0.6 ml) was added to a mixture oftert-butyl{(1S)-1-[(4R)-2,2-dimethyl-4-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(100 mg) and DOX (1 ml) and the mixture was stirred at room temperaturefor 4.5 hours. The resulting reaction mixture was concentrated underreduced pressure and the residue was purified by ODS columnchromatography (MeCN/0.1% aqueous formic acid solution). CH₂Cl₂ (1 ml)and hydrogen chloride (4 M DOX solution, 0.2 ml) were added to theobtained compound. The solvent was distilled off from the obtainedmixture under reduced pressure to give(5R)-5-[(1S)-1-amino-3-methylbutyl]-2,2-dimethyl-5-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-1,3-dioxolan-4-onedihydrochloride (72 mg) as a solid.

Example 9

A mixture of(3R,4S)-4-(2-cyclobutylethyl)-3-([4-(2-cyclopropylethoxy)pyridin-2-yl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(212 mg), THF (5 ml) and 6 M hydrochloric acid (1 ml) was stirred at 60°C. for 1 hour. The resulting reaction mixture was allowed to cool toroom temperature and subsequently concentrated under reduced pressure.The resulting residue was purified by ODS column chromatography(MeCN/0.1% aqueous formic acid solution) to give(2R,3S)-3-amino-5-cyclobutyl-2-{[4-(2-cyclopropylethoxy)pyridin-2-yl]methyl}-2-hydroxypentanoicacid (124 mg) as a solid.

Example 10

Under argon atmosphere, a mixture of(2R,3S)-3-amino-3-(4-bromophenyl)-2-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-2-hydroxypropanoicacid (191 mg), zinc cyanide (250 mg),bis(tri-tert-butylphosphine)palladium (0) (87 mg), zinc (5 mg) andN,N-dimethylacetamide (3.8 ml) was stirred at 95° C. overnight. Aftercooling the resulting reaction mixture to room temperature, water wasadded thereto and the mixture was extracted twice with CH₂Cl₂. Theobtained organic layer was combined, washed sequentially with water anda saturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.Water was added to the resulting residue, and the insoluble materialswere removed by filtration and the filtrate was purified by ODS columnchromatography (MeCN/0.1% aqueous formic acid solution). An excessamount of 1 M hydrochloric acid was added to the obtained compound andthe solvent was distilled off under reduced pressure to give(2R,3S)-3-amino-3-(4-cyanophenyl)-2-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-2-hydroxypropanoicacid dihydrochloride (76 mg) as a solid.

Example 11

Under argon atmosphere, a mixture of(2R,3S)-3-amino-4-(2-bromophenoxy)-2-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-2-hydroxybutanoicacid (141 mg), zinc cyanide (345 mg),bis(tri-tert-butylphosphine)palladium (0) (150 mg), zinc (19 mg) andN,N-dimethylacetamide (2.8 ml) was stirred at 95° C. for 8 hours. Waterwas added to the resulting reaction mixture and the mixture wasextracted twice with CH₂Cl₂. The obtained organic layers were combined,dried over anhydrous magnesium sulfate and the solvent was distilled offunder reduced pressure. 1 M Hydrochloric acid and AcOEt were added tothe resulting residue. The organic layer and the aqueous layer wereseparated and the obtained aqueous layer was purified by ODS columnchromatography (MeCN/0.1% aqueous formic acid solution) to give(2R,3S)-3-amino-4-(2-cyanophenoxy)-2-([4-(cyclohexyloxy)pyridin-2-yl]methyl)-2-hydroxybutanoicacid (58 mg) as a solid.

Example 12

A mixture of(15S,16R)-15-amino-16-hydroxy-2,13-dioxa-19-azabicyclo[16.3.1]docosa-1(22),7,18,20-tetraene-16-carboxylicacid dihydrochloride (30 mg), EtOH (10 ml) and 10% Pd/C (50% watercontent, 50 mg) was stirred at room temperature for 3 hours underhydrogen atmosphere of 3 atm. Celite was added to the resulting reactionmixture, and the insoluble materials were removed by filtration. Theobtained filtrate was concentrated under reduced pressure and theresidue was purified by ODS column chromatography (MeCN/0.1% aqueousformic acid solution). An excess amount of 1 M hydrochloric acid wasadded to the obtained compound and the solvent was distilled off underreduced pressure to give(15S,16R)-15-amino-16-hydroxy-2,13-dioxa-19-azabicyclo[16.3.1]docosa-1(22),18,20-toriene-16-carboxylic acid dihydrochloride (18 mg) as a solid.

Example 13

Piperidine (0.11 ml) was added to a mixture of(2R,3S)-3-amino-2-[(4-chloropyridin-2-yl)methyl]-2-hydroxy-5-methylhexanoicacid (30 mg) and water (0.6 ml) and the mixture was stirred at 130° C.for 1 hour under microwave irradiation. The resulting reaction mixturewas cooled with an ice-water bath, subsequently 1 M hydrochloric acid(1.2 ml) was added thereto and purified by ODS column chromatography(MeCN/0.1% aqueous formic acid solution). An excess amount of 1 Mhydrochloric acid was added to the obtained compound and the solvent wasdistilled off under reduced pressure to give(2R,3S)-3-amino-2-hydroxy-5-methyl-2-{[4-(piperidin-1-yl)pyridin-2-yl]methyl}hexanoicacid dihydrochloride (25.6 ml) as a solid.

Example 14

CMBP (0.23 ml) was added to a mixture of(3R,4S)-3-[(4-hydroxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(100 mg), 1-naphthylmethanol (140 mg) and toluene (2 ml) and the mixturewas stirred at 110° C. overnight. The resulting reaction mixture wasconcentrated under reduced pressure. DOX (1 ml) and 6 M hydrochloricacid (1 ml) were added to the resulting residue and the mixture wasstirred at 60° C. overnight. Water was added to the resulting reactionmixture and the mixture was washed with AcOEt. The obtained aqueouslayer was concentrated under reduced pressure. The resulting residue waspurified by ODS column chromatography (MeCN/0.1% aqueous formic acidsolution). After adding an excess amount of 1 M hydrochloric acid to theobtained compound, the solvent was distilled off under reduced pressureto give(2R,3S)-3-amino-2-hydroxy-5-methyl-2-{[4-(1-naphthylmethoxy)pyridin-2-yl]methyl}hexanoicacid dihydrochloride (55.6 mg) as a solid.

Example 15

CMBP (0.35 ml) was added to a mixture of(3R,4S)-3-[(4-hydroxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(150 mg), 2-(1-methyl-1H-pyrazol-4-yl)ethanol (170 mg) and toluene (3ml) and the mixture was stirred at 90° C. overnight. The resultingreaction mixture was allowed to cool to room temperature andsubsequently concentrated under reduced pressure. DOX (1 ml) and 6 Mhydrochloric acid (3 ml) were added to the resulting residue and themixture was stirred at 60° C. for 3 hours. After cooling the resultingreaction mixture to room temperature, water was added thereto and themixture was washed with AcOEt. The obtained aqueous layer wasconcentrated under reduced pressure and the residue was purified by ODScolumn chromatography (MeCN/0.1% aqueous formic acid solution) to give(2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[2-(1-methyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}methyl)hexanoicacid (65 mg) as a solid.

Example 16

Under nitrogen atmosphere, CMMP (100 mg) was added to a mixture of(3R,4S)-3-[(4-hydroxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(200 mg), (1 S,2S,3 S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ol (135mg) and toluene (4 ml) and the mixture was stirred at 170° C. for 1 hourunder microwave irradiation. The resulting reaction mixture was allowedto cool to room temperature and subsequently concentrated under reducedpressure. DOX (1.33 ml) and 6 M hydrochloric acid (4 ml) were added tothe resulting residue and the mixture was stirred at 60° C. overnight.After cooling the resulting reaction mixture to room temperature, waterwas added thereto, and the mixture was washed with AcOEt. The obtainedaqueous layer was concentrated under reduced pressure and the residuewas purified by ODS column chromatography (MeCN/0.1% aqueous formic acidsolution). An excess amount of 1 M hydrochloric acid was added to theobtained compound and the solvent was distilled off under reducedpressure to give (2R,3S)-3-amino-2-hydroxy-5-methyl-2-[(4-{[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hepta-3-yl]oxy}pyridin-2-yl)methyl]hexanoicacid dihydrochloride (15 mg) as a solid.

Example 17

(1) 0.2 M Phosphate buffer (30 ml) adjusted pH to 7.7 was added to(2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoicacid dihydrochloride (625 mg), subsequently 1 M aqueous sodium hydroxidesolution was added to adjust a pH of the reaction mixture to about 7.7and the mixture was then stirred at room temperature for 2 hours. Theprecipitate was collected by filtration to give(2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoicacid (509 mg) as a solid. The obtained solid (100 mg) was used for thereaction (2) to be described later. The remaining solid was combinedwith a solid of a same compound separately prepared in the same manner(total 5.27 g). To the solid of the compound was added EtOH (28.5 ml)and water (19 ml), and the mixture was heated to 80° C. and stirreduntil the solid was dissolved. The obtained solution was graduallyallowed to cool to room temperature and stirred for 16 hours. Theprecipitate was collected by filtration to give (2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoicacid (4.29 g) as a crystal. The obtained crystal had a powder X-raydiffraction pattern having peaks at about 2θ (°) 5.2, 10.2, 10.4, 13.6,17.0, 17.5, 18.5, 20.4, 20.9, 21.2 and 23.1.

(2) A mixture of(2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoicacid (100 mg) and MeOH (2 ml) was cooled with an ice-water bath andsubsequently thionyl chloride (0.5 ml) was added thereto with stirring.The resulting reaction mixture was stirred at room temperature for 3days and subsequently concentrated under reduced pressure. The resultingresidue was purified by amino-silica gel column chromatography(hexane/AcOEt). An excess amount of 1 M hydrochloric acid was added tothe obtained compound and the solvent was distilled off under reducedpressure to give methyl(2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoate dihydrochloride (48 mg) as a solid.

Example 18

n-Butanthiol (0.11 ml) was added to a mixture of(2R,3S)-3-amino-2-[(4-chloropyridin-2-yl)methyl]-2-hydroxy-5-methylhexanoicacid (100 mg), DIPEA (0.12 ml), potassium carbonate (150 mg) and DMF (3ml) and the mixture was stirred at 120° C. for 3 hours under microwaveirradiation. After cooling the resulting reaction mixture to roomtemperature, water was added thereto. The obtained mixture was purifiedby ODS column chromatography (MeCN/0.1% aqueous formic acid solution) togive(2R,3S)-3-amino-2-{[4-(butylsulphanyl)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoicacid (15 mg) as a solid.

Example 19

A mixture of(2R,3S)-3-amino-2-[(4-chloropyridin-2-yl)methyl]-2-hydroxy-5-methylhexanoicacid (50 mg), 2-naphthol (126 mg), cesium carbonate (284 mg) andN,N-dimethylacetamide (1.5 ml) was stirred at 150° C. for 2 hours undermicrowave irradiation. The resulting reaction mixture was allowed tocool to room temperature, subsequently diluted with water and washedtwice with diethyl ether. 1 M Hydrochloric acid (1.9 ml) was added tothe obtained aqueous layer and subsequently purified by ODS columnchromatography (MeCN/0.1% aqueous formic acid solution). MeCN and anexcess amount of 1 M hydrochloric acid were added to the obtainedcompound and the solvent was distilled off under reduced pressure togive(2R,3S)-3-amino-2-hydroxy-5-methyl-2-([4-(2-naphthyloxy)pyridin-2-yl]methyl)hexanoic acid dihydrochloride (10.4 mg) as a solid.

Example 20

1 M Aqueous sodium hydroxide solution (0.25 ml) was added to a mixtureof tert-butyl{(1S)-1-[(4R)-4-{[2-(2-cyclopropylethyl)furo[3,2-c]pyrridin-4-yl]methyl}-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(10 mg), DOX (0.25 ml) and MeOH (0.25 ml) and the mixture was stirred at50° C. for 5 hours. The resulting reaction mixture was allowed to coolto room temperature and subsequently concentrated under reducedpressure. After adding DOX (0.25 ml) to the resulting residue, hydrogenchloride (4 M DOX solution, 0.25 ml) was added thereto under ice-bathcooling and subsequently the mixture was stirred at room temperature for1 hour. The resulting reaction mixture was cooled again with anice-water bath, 1 M aqueous sodium hydroxide solution (0.5 ml) and DOXwere added thereto and the mixture was concentrated under reducedpressure. The resulting residue was purified by ODS columnchromatography (MeCN/0.1% aqueous formic acid solution) to give(2R,3S)-3-amino-2-{[2-(2-cyclopropylethyl)furo[3,2-c]pyridin-4-yl]methyl}-2-hydroxy-5-methylhexanoicacid (5 mg) as a solid.

Examples 21 to 101

Example compounds shown in Tables to be described later were produced inthe same manner as in the method described in the above Examples.

Example 102

Under argon atmosphere, a mixture of(3R,4S)-3-[(4-chloropyridin-2-yl)methyl]-4-[(4-fluorophenoxy)methyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(300 mg), N-(2,2,2-trifluoroethyl)cyclohexaneamine hydrochloride (270mg), tris(dibenzylideneacetone)dipalladium (129 mg),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (135 mg),sodium tert-butoxide (390 mg) and toluene (12 ml) was stirred at 120° C.for 1 hour under microwave irradiation. The resulting reaction mixturewas allowed to cool to room temperature and subsequently purified bysilica gel column chromatography (hexane/AcOEt) to give(3R,4S)-3-({4-[cyclohexyl(2,2,2-trifluoroethyl)amino]pyridin-2-yl}methyl)-4-[(4-fluorophenoxy)methyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(150 mg) as an oily product.(2R,3S)-3-Amino-2-({4-[cyclohexyl(2,2,2-trifluoroethyl)amino]pyridin-2-yl}methyl)-4-(4-fluorophenoxy)-2-hydroxybutanoic acid dihydrochloride (15 mg) was prepared as a solid from theabove oily product (80 mg) in the same manner as in the method describedin Example 6.

Example 103

A mixture ofS-{[(2R,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-oxoazetidin-2-yl]methyl}thioacetate(200 mg), MeOH (2 ml), DMF (2 ml), methyl iodide (0.08 ml) and potassiumcarbonate (180 mg) was stirred at room temperature for 2 hours. Waterwas added to the resulting reaction mixture. The mixture was extractedwith AcOEt and subsequently concentrated under reduced pressure. MeOH (2ml) and 6 M aqueous sodium hydroxide solution (1 ml) were added to theresulting residue and the mixture was stirred at 60° C. overnight. Aftercooling the resulting reaction mixture to room temperature, the mixturewas concentrated under reduced pressure. DOX (2 ml) and 6 M hydrochloricacid (3 ml) were added to the resulting residue under ice-bath cooling.The resulting reaction mixture was stirred at room temperature for 5hours and subsequently concentrated under reduced pressure. Theresulting residue was purified by ODS column chromatography (MeCN/0.1%aqueous formic acid solution) to give(2R,3R)-3-amino-2-hydroxy-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-(methylsulfanyl)butanoicacid (100 mg) as a solid.

Example 104

A mixture of S-{[(2R,3R)-3-({4-[(2R)-hexan-2-yloxy]pyridin-2-yl}methyl)-3-(methoxymethoxy)-1-(methoxymethyl)-4-oxoazetidin-2-yl]methyl}thioacetate(100 mg), MeOH (1 ml), DMF (1 ml), 1-iodo-2-methylpropane (0.08 ml) andpotassium carbonate (100 mg) was stirred at room temperature overnight.Water was added to the resulting reaction mixture. The mixture wasextracted with AcOEt and subsequently concentrated under reducedpressure. MeOH (1 ml) and 6 M aqueous sodium hydroxide solution (1 ml)were added to the resulting residue and the resulting reaction mixturewas stirred at 60° C. for 3 hours. The resulting reaction mixture wasallowed to cool to room temperature and subsequently concentrated underreduced pressure. DOX (1 ml) and 6 M hydrochloric acid (3 ml) were addedto the resulting residue and the resulting reaction mixture was stirredat room temperature overnight and subsequently concentrated underreduced pressure. The resulting residue was purified by ODS columnchromatography (MeCN/0.1% aqueous formic acid solution). An excessamount of 1 M hydrochloric acid was added to the obtained compound andthe solvent was distilled off under reduced pressure to give(2R,3R)-3-amino-2-({4-[(2R)-hexan-2-yloxy]pyridin-2-yl}methyl)-2-hydroxy-4-(isobutylsulfanyl)butanoicacid dihydrochloride (48 mg) as a solid.

Example 105

3 M Hydrochloric acid (6 ml) was added to a mixture of(3R,4R)-4-[(ethylsulfanyl)methyl]-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(598 mg) and DOX (1.5 ml) and the mixture was stirred at 60° C. for 2hours. After adding 6 M aqueous sodium hydroxide solution (1.5 ml) tothe resulting reaction mixture under ice-bath cooling, the mixture wasconcentrated under reduced pressure. The resulting residue was dissolvedin water (10 ml) and a pH of the solution was adjusted to about 2.0 with6 M aqueous sodium hydroxide solution. After adding EtOH (3 ml), a pH ofthe solution was adjusted to about 7.0 with 6 M aqueous sodium hydroxidesolution and 1 M hydrochloric acid. The obtained mixture was stirred atroom temperature for 15 hours. The precipitate was collected byfiltration and washed with water to give(2R,3R)-3-amino-4-(ethylsulfanyl)-2-hydroxy-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)butanoicacid (417 mg) as a crystal. The obtained crystal had a powder X-raydiffraction pattern having peaks at about 2θ(°) 5.1, 13.8, 17.6, 18.2,18.5, 18.7, 19.1, 20.3, 20.7, 23.4, 24.3 and 25.2.

Examples 106-146

Example compounds shown in Tables to be described later were produced inthe same manner as in the method described in the above Examples.

Tables to be described later show the structure, physicochemical dataand production method of the Example compounds.

Production Example 1

A mixture of(3R,4S)-3-[(4-hydroxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(200 mg), cis-4-methyl cyclohexanol (0.224 ml), CMBP (0.467 ml) andtoluene (4 ml) was stirred at 90° C. overnight. The resulting reactionmixture was allowed to cool to room temperature and subsequentlyconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(35 mg) as an oily product.

Production Example 2

Under nitrogen atmosphere, CMMP (65 mg) was added to a mixture of(3R,4S)-3-[(4-hydroxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(160 mg), (5r,8s)-1-oxaspiro[4.5]decan-8-ol (78 mg) and toluene (2 ml)and the mixture was stirred at 140° C. for 1.5 hours under microwaveirradiation. The resulting reaction mixture was allowed to cool to roomtemperature and subsequently concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane/AcOEt/MeOH) to give(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-3-((4-[(5s,8r)-1-oxaspiro[4.5]deca-8-yloxy]pyridin-2-yl}methyl)azetidin-2-one(63 mg) as an oily product.

Production Example 3

Under argon atmosphere, to a mixture of(3R,4S)-3-hydroxy-4-isobutylazetidin-2-one (38.9 g),chloro(methoxy)methane (90 ml) and THF (778 ml) was added NaH (60%mineral oil dispersion, total 26 g) portionwise (ca.5 g×5 times) over aperiod of 1 hour under ice-bath cooling. After stirring the resultingreaction mixture for 1 hour under ice-bath cooling, 5% aqueous ammoniumchloride solution was added thereto. After separating the organic layer,the aqueous layer was extracted 3 times with AcOEt. The organic layerswere combined and washed sequentially with a saturated aqueous sodiumhydrogen carbonate solution and a saturated aqueous sodium chloridesolution. The organic layer was dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(57.89 g) as an oily product.

Production Example 4

Potassium hexamethyldisilazide (1.0 M THF solution, 1.5 ml) was added toa mixture of(3R,4S)-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-(methoxymethoxy)azetidin-2-one(302 mg), chloro(methoxy)methane (0.15 ml), tetra-n-butylammonium iodide(500 mg) and THF (9 ml) under ice-bath cooling, the mixture was stirredfor 1 hour and then stirred at room temperature overnight. Water wasadded to the resulting reaction mixture and the mixture was extractedwith AcOEt. The obtained organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane/AcOEt)to give(3R,4S)-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(247 mg) as an oily product.

Production Example 5

A saturated aqueous sodium hydrogen carbonate solution was added to amixture of 4-(benzyloxy)-2-(chloromethyl)pyridine hydrochloride (17.5 g)and CHCl₃. After separating the organic layer from the obtained mixture,the aqueous layer was extracted with CHCl₃. The obtained organic layerswere combined, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. Sodium iodide (20 g) was added to a mixture ofthe obtained oily product, THF (100 ml) and acetone (100 ml) at roomtemperature. After stirring at room temperature for 1 hour, the mixturewas diluted with toluene. The resulting mixture was concentrated toabout 50 ml under reduced pressure and toluene and anhydrous magnesiumsulfate were added to the obtained mixture. The insoluble material wasremoved by filtration and the obtained filtrate was concentrated againto about 50 ml under reduced pressure (mixture A).

Under argon atmosphere, LDA (1.12 M hexane-THF solution, 60 ml) wasadded dropwise with stirring to a mixture of(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(10 g) and THF (200 ml) at −78° C. The resulting reaction mixture wasstirred at the same temperature for 30 minutes and subsequently themixture A was added dropwise at the same temperature. The mixture wasstirred at the same temperature for 3 hours and subsequently allowed towarm up to room temperature. After cooling the resulting reactionmixture to 0° C., water was added thereto and the mixture was extractedwith AcOEt. The obtained organic layer was dried over anhydrousmagnesium sulfate. The obtained organic layer was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (hexane/AcOEt) to give (3R,4S)-3-{[4-(benzyloxy)pyridin-2-yl]methyl}-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(14.5 g) as an oily product.

Production Example 6

Under ice-bath cooling, thionyl chloride (17 ml) was added to a mixtureof [4-(benzyloxy)pyridin-2-yl]methanol (23.6 g) and CH₂Cl₂(500 ml). Theresulting reaction mixture was allowed to warm up to room temperatureand stirred overnight. The resulting reaction mixture was concentratedunder reduced pressure and toluene was added to the residue. Theobtained mixture was concentrated under reduced pressure and theresulting residue was washed with diisopropyl ether to give4-(benzyloxy)-2-(chloromethyl)pyridine hydrochloride (24.9 g) as asolid.

Production Example 7

Under argon atmosphere, 10% Pd/C (50% water content, 1.45 g) was addedto a mixture of(3R,4S)-3-([4-(benzyloxy)pyridin-2-yl]methyl}-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(14.5 g) and MeOH (200 ml) and subsequently the mixture was stirredovernight under hydrogen atmosphere. The resulting reaction mixture wasfiltered through Celite and the filtrate was concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (CHCl₃/MeOH) to give(3R,4S)-3-[(4-hydroxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(9.8 g) as an oily product.

Production Example 8

Under argon atmosphere, a mixture of(3R,4S)-3-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(250 mg), CMBP (280 mg), 2-bromophenol (220 mg) and toluene (6 ml) wasstirred at 90° C. for 8 hours. The resulting reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (hexane/AcOEt) to give(3R,4S)-4-[(2-bromophenoxy)methyl]-3-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(338 mg) as a solid.

Production Example 9

NaH (60% mineral oil dispersion, 3.0 g) was added to a mixture of2-cyclopropylethanol (5.04 g) and DMF (90 ml) under ice-bath cooling andthe mixture was stirred for 30 minutes. A solution of4-chloropyridine-2-carbonitrile (8.6 g) in DMF (10 ml) was added to theresulting reaction mixture and the mixture was stirred at roomtemperature for 2 hours. Water was added to the resulting reactionmixture under ice-bath cooling and the mixture was extracted with AcOEt.The obtained organic layer was washed with a saturated aqueous sodiumchloride solution and subsequently dried over anhydrous magnesiumsulfate. The organic layer was concentrated under reduced pressure andthe resulting residue was purified by silica gel column chromatography(hexane/AcOEt) to give 4-(2-cyclopropylethoxy)pyridine-2-carbonitrile(6.76 g) as a solid.

Production Example 10

Sodium methoxide (28% MeOH solution, 7.2 ml) was added to a mixture of4-(2-cyclopropylethoxy)pyridine-2-carbonitrile (6.76 g) and MeOH (140ml) under ice-bath cooling and the mixture was stirred at roomtemperature for 3 hours. 1 M Hydrochloric acid (120 ml) was added to theresulting reaction mixture and the mixture was stirred for 1 hour. Theresulting reaction mixture was concentrated under reduced pressure andAcOEt and a saturated aqueous sodium hydrogen carbonate solution wereadded to the resulting residue. The organic layer was separated from theobtained mixture and the aqueous layer was extracted with AcOEt. Theobtained organic layer was washed with a saturated aqueous sodiumchloride solution and subsequently dried over anhydrous sodium sulfate.The organic layer was concentrated under reduced pressure, NaBH₄ (4.0 g)was added to a mixture of the resulting residue and MeOH (150 ml) underice-bath cooling and the mixture was stirred at room temperatureovernight. The resulting reaction mixture was concentrated under reducedpressure and a saturated aqueous ammonium chloride solution was added tothe residue and the mixture was extracted with AcOEt. The organic layerwas washed with a saturated aqueous sodium chloride solution andsubsequently dried over anhydrous magnesium sulfate. The obtainedorganic layer was concentrated under reduced pressure and the resultingresidue was purified by silica gel column chromatography (CHCl₃/MeOH) togive [4-(2-cyclopropylethoxy)pyridin-2-yl]methanol (5.89 g) as an oilyproduct.

Production Example 11

Under argon atmosphere, cyclopropylmethylbromide (0.03 ml) was added toa mixture of(3R,4R)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-(sulfanylmethyl)azetidin-2-one(120 mg), potassium carbonate (50 mg), sodium iodide (100 mg) and DMF (5ml) and the mixture was stirred at room temperature overnight. Asaturated aqueous sodium chloride solution was added to the resultingreaction mixture and the mixture was extracted with AcOEt. The obtainedorganic layer was washed with a saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane/AcOEt) to give(3R,4R)-4-{[(cyclopropylmethyl)sulphanyl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(39.7 mg) as an oily product.

Production Example 12

AcOH (0.0176 ml) andN-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethaneaminiumhexafluorophosphate (71 mg) were added under ice-bath cooling to amixture of(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-3-{[4-(piperidin-4-yloxy)pyridin-2-yl]methyl}azetidin-2-one(65 mg) and DMF (1 ml). After stirring the resulting reaction mixture atroom temperature for 1 hour, water was added thereto and the mixture wasextracted twice with CHCl₃. The obtained organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(CHCl₃/MeOH) to give(3R,4S)-3-({4-[(1-acetylpiperidin-4-yl)oxy]pyridin-2-yl}methyl)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(49 mg) as an oily product.

Production Example 13

Under nitrogen atmosphere, a mixture of(3R,4S)-3-[(4-chloropyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(200 mg), trans-4-methylcyclohexanecarboxamide (90 mg),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (65 mg),tris(dibenzylideneacetone)dipalladium (50 mg), cesium carbonate (200 mg)and DOX (4 ml) was stirred at 110° C. for 20 hours. The resultingreaction mixture was concentrated under reduced pressure and the residuewas purified by silica gel column chromatography (hexane/AcOEt) to givetrans-N-(2-{[(2S,3R)-2-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-4-oxoazetidin-3-yl]methyl}pyridin-4-yl)-4-methylcyclohexanecarboxamide(137 mg) as an oily product.

Production Example 14

A mixture of 2,5-dimethyl-4-nitropyridine 1-oxide (2 g), benzyl alcohol(6.7 ml), potassium carbonate (3.3 g), benzyltri-n-butylammoniumchloride (700 mg) and water (10.5 ml) was stirred at 160° C. for 1 hourunder microwave irradiation. After cooling the resulting reactionmixture to room temperature, water was added thereto and the mixture wasextracted three times with CHCl₃. The obtained organic layer was driedover anhydrous magnesium sulfate and subsequently concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (CHCl₃/MeOH) to give4-(benzyloxy)-2,5-dimethylpyridin 1-oxide (1.9 g) as a solid.

Production Example 15

A mixture of 4-(benzyloxy)-2,5-dimethylpyridin 1-oxide (4.3 g) andacetic anhydride (80 ml) was stirred at 80° C. for 1 hour. The resultingreaction mixture was allowed to cool to room temperature andsubsequently concentrated under reduced pressure. MeOH (70 ml) andpotassium carbonate (6 g) were added to the resulting residue and themixture was stirred at room temperature for 1 hour. Water was added tothe resulting reaction mixture and the mixture was extracted with CHCl₃.The organic layer was dried over anhydrous magnesium sulfate andsubsequently concentrated under reduced pressure. The resulting residuewas purified by amino-silica gel column chromatography (hexane/AcOEt) togive [4-(benzyloxy)-5-methylpyridin-2-yl]methanol (1.94 g) as a solid.The obtained compound was combined with a same compound separatelyprepared in the same manner. Thionyl chloride (2.4 ml) was added withstirring under ice-bath cooling to a mixture of the obtained[4-(benzyloxy)-5-methylpyridin-2-yl]methanol (3.56 g) and CH₂Cl₂ (70 ml)and the mixture was stirred at room temperature for 2 hours. Theresulting reaction mixture was concentrated under reduced pressure andtoluene was added to the residue. The solvent was distilled off from theobtained mixture under reduced pressure to give4-(benzyloxy)-2-(chloromethyl)-5-methylpyridine hydrochloride (4.41 g)as a solid.

Production Example 16

After cooling a mixture of5-[(benzyloxy)methyl]-4-methoxy-2-methylpyridine (500 mg) and CH₂Cl₂ (10ml) with an ice-water bath, m-chloroperbenzoic acid (about 25% watercontent, 532 mg) was added thereto and the mixture was stirred at roomtemperature for 2 hours. Aqueous sodium thiosulfate solution was addedto the resulting reaction mixture and the mixture was stirred at roomtemperature for 15 minutes. After separating the aqueous layer from theorganic layer, the organic layer was washed sequentially with water anda saturated aqueous sodium chloride solution. The obtained organic layerwas dried over anhydrous magnesium sulfate and subsequently concentratedunder reduced pressure. AcOH (1 ml) and acetic anhydride (1 ml) wereadded to the resulting residue and the mixture was stirred at 100° C.for 3 hours. The resulting reaction mixture was allowed to cool to roomtemperature and subsequently concentrated under reduced pressure. MeOH(5.0 ml) and 6 M aqueous sodium hydroxide solution (1 ml) were added tothe resulting residue and the mixture was stirred at room temperatureovernight. Water was added to the resulting reaction mixture and themixture was extracted with CHCl₃. The obtained organic layer was driedover anhydrous magnesium sulfate and subsequently concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (CHCl₃/MeOH) to give{5-[(benzyloxy)methyl]-4-methoxypyridin-2-yl}methanol (380 mg) as anoily product.

Production Example 17

A mixture of 4-[(2-{[(2S,3R)-2-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-4-oxoazetidin-3-yl]methyl}pyridin-4-yl)oxy]piperidine-1-benzylcarboxylate (216 mg), 10% Pd/C (50% water content, 22 mg) and EtOH (5ml) was stirred at room temperature for 4 hours under hydrogenatmosphere. Insoluble material was removed by filtration from theresulting reaction mixture and subsequently the filtrate wasconcentrated under reduced pressure. MeOH (5 ml) and 10% Pd/C (50% watercontent, 49 mg) were added to the resulting residue and the mixture wasstirred at room temperature for 3 hours under hydrogen atmosphere.Insoluble material was removed by filtration from the resulting reactionmixture and subsequently the filtrate was concentrated under reducedpressure to give(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-3-{[4-(piperidin-4-yloxy)pyridin-2-yl]methyl}azetidin-2-one(157 mg) as an oily product.

Production Example 18

A mixture of 2,3,5-trimethyl-4-(2-phenylethoxy)pyridin 1-oxide (510 mg),4-methylbenzenesulfonyl chloride (570 mg) and MeCN (8 ml) was stirred at40° C. for 1 hour. Et₃N (0.43 ml) was added to the reaction mixture withstirring and the mixture was stirred at 40° C. for 3 hours. Aftercooling the resulting reaction mixture to room temperature, a saturatedaqueous sodium hydrogen carbonate solution was added thereto and themixture was extracted with CHCl₃. The obtained organic layer was washedwith a saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and subsequently concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(hexane/AcOEt) to give2-(chloromethyl)-3,5-dimethyl-4-(2-phenylethoxy)pyridine (370 mg) as anoily product.

Production Example 19

A mixture of (4-methoxy-6-methylpyridin-3-yl)methanol (2.4 g) and DMF(20 ml) was cooled with an ice-water bath, subsequently NaH (55% mineraloil dispersion, 750 mg) was added thereto and the mixture was stirred atthe same temperature for 1 hour. A mixture of benzyl bromide (4 ml) andDMF (4 ml) was added to the reaction mixture and the mixture was stirredat room temperature overnight. Water was added to the resulting reactionmixture and the mixture was extracted with CHCl₃. The obtained organiclayer was dried over anhydrous magnesium sulfate and subsequentlyconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (CHCl₃/MeOH) to give5-[(benzyloxy)methyl]-4-methoxy-2-methylpyridine (1 g) as an oilyproduct.

Production Example 20

Under nitrogen atmosphere, NaBH₄ (270 mg) was added under ice-bathcooling to a mixture of1-(2-cyclohexylethyl)-1H-imidazo[4,5-c]pyridine-6-methyl carboxylate(640 mg) and MeOH (9 ml) and the mixture was stirred at the sametemperature for 30 minutes. The resulting reaction mixture was allowedto warm up to room temperature and stirred overnight. The resultingreaction mixture was cooled with an ice-water bath. A saturated aqueousammonium chloride solution was added thereto and the mixture wasextracted three times with CH₂Cl₂. The obtained organic layer was washedwith a saturated aqueous sodium chloride solution and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to give[1-(2-cyclohexylethyl)-1H-imidazo[4,5-c]pyridin-6-yl]methanol (560 mg)as an oily product.

Production Example 21

A mixture of(2S,3R)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoic acid(4 g), 1,2-dichloroethane (20 ml), 2,2-dimethoxypropane (20 ml) andpyridinium p-toluenesulfonate (385 mg) was stirred at 80° C. overnight.After cooling the resulting reaction mixture to room temperature, asaturated aqueous sodium hydrogen carbonate solution was added theretoand the mixture was extracted with AcOEt. The obtained organic layer wasdried over anhydrous magnesium sulfate and subsequently concentratedunder reduced pressure. EtOH and water were added to the resultingresidue and the mixture was heated to 60° C. The obtained mixture wasallowed to cool to room temperature and subsequently the precipitate wascollected by filtration and washed with water to give tert-butyl((1R)-1-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(3.4 g) as a solid.

Production Example 22

After cooling a mixture of{4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methanol (9.3 g) and THF(70 ml) with an ice-water bath, a mixture of PBr₃ (4.2 ml) and THF (20ml) was added dropwise and the mixture was stirred at room temperaturefor 3 hours. The resulting reaction mixture was cooled with an ice-waterbath. MeOH (46.5 ml) was added dropwise and the mixture was stirred atroom temperature for 30 minutes. Activated carbon (1 g) was added to thereaction mixture and the mixture was stirred at room temperature for 30minutes. Celite was added to the reaction mixture and the insolublematerial was removed by filtration through Celite. The obtained filtratewas concentrated under reduced pressure. AcOEt was added to theresulting residue and the mixture was stirred at room temperature for 1hour. Diisopropyl ether was added dropwise to the obtained mixture andthe mixture was stirred at room temperature for 5 hours. The precipitatewas collected by filtration and rinsed with a mixture ofAcOEt-diisopropyl ether (2:1) and diisopropyl ether to give2-(bromomethyl)-4-[(trans-4-methylcyclohexyl)oxy]pyridine hydrobromate(13.8 g) as a solid.

Production Example 23

A mixture of 2-(bromomethyl)-4-[(trans-4-methylcyclohexyl)oxy]pyridinehydrobromate (7.5 g) and THF (35 ml) was cooled to −78° C., lithiumhexamethyldisilazide (1.3 M hexane solution, 16 ml) was added dropwisethereto under argon atmosphere and the mixture was stirred at the sametemperature for 30 minutes. The resulting reaction mixture was warmed upto 0° C. and stirred for 30 minutes (mixture A).

Under argon atmosphere, a mixture of(3R,4S)-3-(methoxymethoxy)-1-(methoxymethyl)-4-[(triisopropylsilyl)oxy]methyl}azetidin-2-one(7 g) and THF (28 ml) was cooled to −78° C., LDA (1.09 M hexane-THFsolution, 37 ml) was added dropwise thereto and the mixture was stirredfor 30 minutes. The mixture A was added to the resulting reactionmixture and the mixture was stirred for 2 hours. A mixture of AcOH (2.1ml) and THF (7 ml) was added to the resulting reaction mixture at −78°C. and the mixture was stirred for 15 minutes. The resulting reactionmixture was warmed up to 0° C. Dimethylamine (2 M THF solution, 19.4 ml)was added thereto and the mixture was stirred for 30 minutes. Theresulting reaction mixture was poured into a mixture of water and AcOEtand the organic layer was separated. The obtained organic layer waswashed sequentially with 1 M hydrochloric acid, a saturated aqueoussodium hydrogen carbonate solution and a saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate andsubsequently concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-{[(triisopropylsilyl)oxy]methyl}azetidin-2-one(7.1 g) as an oily product.

Production Example 24

A solution of PBr₃ (1.17 ml) in CH₂Cl₂(10 ml) was added dropwise underice-bath cooling to a solution of{4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methanol (3.44 g) inCH₂Cl₂ (42 ml). The reaction mixture was stirred at room temperature for1.5 hours and subsequently added to an ice-cooled mixture of a saturatedaqueous sodium hydrogen carbonate solution and CH₂Cl₂. The obtainedmixture was stirred at room temperature for 20 minutes and subsequentlyextracted with CH₂Cl₂. The obtained organic layer was washed with asaturated aqueous sodium chloride solution, subsequently dried overanhydrous magnesium sulfate, diluted with toluene and concentrated underreduced pressure to about 20 ml. The obtained mixture was diluted againwith toluene and concentrated again under reduced pressure to about 25ml (mixture A).

Under nitrogen atmosphere, a solution of tert-butyl{(1S)-1-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(3.12 g) in THF (62 ml) was cooled with a dry ice-acetone bath and LDA(1.09 M hexane—THF solution, 22 ml) was added dropwise thereto. Theresulting reaction mixture was stirred for 40 minutes while cooled withthe dry ice-acetone bath. The mixture A was added dropwise and themixture was further stirred for 2 hours. AcOH was added to the resultingreaction mixture. The mixture was allowed to warm up to room temperatureand AcOEt was added thereto. The obtained mixture was washed with asaturated aqueous sodium carbonate solution and a saturated aqueoussodium chloride solution, subsequently dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/AcOEt) to givetert-butyl{(1S)-1-[(4R)-2,2-dimethyl-4-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(3.63 g) as a foamy solid.

Production Example 25

1H-Benzotriazole-1-methanol (35 mg) was added to a mixture of(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-3-{[4-(piperidin-4-yloxy)pyridin-2-yl]methyl}azetidin-2-one(65 mg) and MeCN (1 ml) and the mixture was stirred at room temperaturefor 10 minutes. Triacetoxysodium borohydride (50 mg) was added to theresulting reaction mixture and the mixture was further stirred at roomtemperature for 50 minutes. A saturated aqueous ammonium chloridesolution was added to the resulting reaction mixture under ice-bathcooling and the mixture was extracted three times with CHCl₃-MeOH (5:1).The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (CHCl₃/MeOH) to give(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(1-methylpiperidin-4-yl)oxy]pyridin-2-yl}methyl)azetidin-2-one (56 mg) as an oily product.

Production Example 26

(2R,3S)-3-amino-2-[(4-chloropyridin-2-yl)methyl]-2-hydroxy-5-methylhexanoicacid (198 mg) was prepared as a solid from(3R,4S)-3-[(4-chloropyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(382 mg) in the same manner as in the method described in Example 9.

Production Example 27

A mixture of(3R,4S)-4-(2-cyclobutylethyl)-3-(methoxymethoxy)azetidin-2-one (517 mg),1,2-dichloroethane (13 ml), chloro(methoxy)methane (0.8 ml) and DIPEA (2ml) was stirred at 90° C. for 12 hours. The resulting reaction mixturewas allowed to cool to room temperature. Chloro(methoxy)methane (0.35ml) and DIPEA (0.83 ml) were added thereto and the mixture was stirredat 90° C. for 5 hours. The resulting reaction mixture was allowed tocool to room temperature. A saturated aqueous sodium hydrogen carbonatesolution was added thereto and the mixture was extracted with AcOEt. Theobtained organic layer was washed with a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate. Theorganic layer was concentrated under reduced pressure and the resultingresidue was purified by silica gel column chromatography (hexane/AcOEt)to give(3R,4S)-4-(2-cyclobutylethyl)-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(512 mg) as an oily product.

Production Example 28

Ammonium cerium (IV) nitrate (4.7 g) was added to a mixture of(3R,4S)-4-(2-cyclobutylethyl)-3-(methoxymethoxy)-1-(4-methoxyphenyl)azetidin-2-one (960 mg),MeCN (24 ml) and water (12 ml) under ice-bath cooling and the mixturewas stirred for 30 minutes. Water and a saturated aqueous sodiumhydrogen carbonate solution were added to the resulting reaction mixturewith stirring and subsequently a 2% aqueous sodium hydrogen sulfitesolution was added thereto. The resulting reaction mixture was filteredthrough Celite and the filtrate was extracted with CHCl₃. The obtainedorganic layer was washed with a saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and subsequentlyconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-4-(2-cyclobutylethyl)-3-(methoxymethoxy)azetidin-2-one (459 mg)as a solid.

Production Example 29

A mixture of(3R,4S)-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-(methoxymethoxy)-1-(4-methoxyphenyl)azetidin-2-one(3.2 g), AcOH (50 ml) and water (13 ml) was stirred at 50° C. for 4hours. The resulting reaction mixture was allowed to cool to roomtemperature and subsequently concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(CHCl₃/MeOH) to give(3R,4S)-4-[(1S)-1,2-dihydroxyethyl]-3-(methoxymethoxy)-1-(4-methoxyphenyl)azetidin-2-one(2.6 g) as an oily product.

Production Example 30

Sodium periodate (2.3 g) was added to a mixture of(3R,4S)-4-[(1S)-1,2-dihydroxyethyl]-3-(methoxymethoxy)-1-(4-methoxyphenyl)azetidin-2-one(2.1 g), CH₂Cl₂ (40 ml) and a saturated aqueous sodium hydrogencarbonate solution (1 ml) and the mixture was stirred at roomtemperature for 1 hour. Anhydrous magnesium sulfate was added to theresulting reaction mixture and the mixture was stirred for 30 minutes.The resulting reaction mixture was filtered through Celite and thesolvent was distilled off from the filtrate under reduced pressure togive(2R,3R)-3-(methoxymethoxy)-1-(4-methoxyphenyl)-4-oxoazetidin-2-carbaldehyde(1.8 g) as a solid.

Production Example 31

NaBH₄ (1.2 g) was added to a mixture of(2R,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-4-oxoazetidin-2-carbaldehyde(5.1 g) and THF (50 ml) under ice-bath cooling and the mixture wasstirred for 30 minutes. After adding water (5 ml) to the resultingreaction mixture, anhydrous magnesium sulfate was added thereto and themixture was stirred at room temperature for 30 minutes. The resultingreaction mixture was filtered and subsequently the filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (CHCl₃/MeOH) to give(3R,4S)-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(4.4 g) as an oily product.

Production Example 32

A mixture of(3R,4S)-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(100 mg), triisopropylchlorosilane (0.21 ml), imidazole (140 mg) and DMF(2 ml) was stirred at room temperature overnight. The resulting reactionmixture was added to water and the mixture was extracted with AcOEt. Theobtained organic layer was washed with a saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate andsubsequently concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-3-(methoxymethoxy)-1-(methoxymethyl)-4-{[(triisopropylsilyl)oxy]methyl}azetidin-2-one(137 mg) as an oily product.

Production Example 33

After cooling a mixture of(3R,4S)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl-4-{[(triisopropylsilyl)oxy]methyl}azetidin-2-one(7.1 g) and THF (100 ml) with an ice-water bath, tetra-n-butylammoniumfluoride (1 M THF solution, 19 ml) was added thereto and the mixture wasstirred for 30 minutes. The reaction mixture was added to a saturatedaqueous ammonium chloride solution and the mixture was extracted withAcOEt. The obtained organic layer was washed with a saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate andsubsequently concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (CHCl₃/MeOH) to give(3R,4S)-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(4.7 g) as an oily product.

Production Example 34

A mixture of (3R,4S)-4-(2-hydroxyethyl)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(200 mg), 1-iodo-2-methylpropane (2 ml) and Ag₂O (1 g) was stirred at90° C. overnight. The resulting reaction mixture was allowed to cool toroom temperature. Insoluble material was removed by filtration and thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-4-(2-isobutoxyethyl)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(80 mg) as an oily product.

Production Example 35

Methanesulfonyl chloride (0.085 ml) was added to a mixture of(3R,4S)-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(222 mg), pyridine (0.175 ml) and CH₂Cl₂ (4 ml) and the mixture wasstirred at room temperature overnight. CH₂Cl₂ was added to the resultingreaction mixture, and the mixture was washed sequentially with 0.5 Mhydrochloric acid, a saturated aqueous sodium hydrogen carbonatesolution and a saturated aqueous sodium chloride solution. The obtainedorganic layer was dried over anhydrous magnesium sulfate and the solventwas distilled off under reduced pressure to give methanesulfonic acid[(2S,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-oxoazetidin-2-yl]methyl(247 mg) as an oily product.

Production Example 36

A mixture of[(2S,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-oxoazetidin-2-yl]methylmethanesulfonate (247 mg), sodium iodide (457 mg) and acetone (10 ml)was refluxed overnight. Sodium iodide (2 g) was added to the resultingreaction mixture and the mixture was refluxed for 13 hours. Aftercooling the resulting reaction mixture to room temperature, water wasadded thereto and the mixture was extracted twice with CH₂Cl₂. Theobtained organic layers were combined, washed with a saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate andsubsequently the solvent was distilled off under reduced pressure togive(3R,4R)-4-(iodomethyl)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(250 mg) as an oily product.

Production Example 37

Under argon atmosphere, a sodium hydrosulfide hydrate (48 mg) was addedto a mixture of(3R,4R)-4-(iodomethyl)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(147 mg) and DMF (2 ml) under ice-bath cooling and the mixture wasstirred for 30 minutes. AcOH was added to the resulting reaction mixtureto acidify. Water was added thereto and the mixture was extracted withAcOEt. The obtained organic layer was dried over anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure to give(3R,4R)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-(sulfanylmethyl)azetidin-2-one(120 mg) as an oily product.

Production Example 38

A mixture of(2R,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-4-oxoazetidine-2-carbaldehyde(3.3 g), (triphenylphosphoranyliden)acetaldehyde (5.5 g) and CH₂Cl₂ (88ml) was stirred at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel column chromatography (hexane/AcOEt) to give amixture of3-[(3R)-3-(methoxymethoxy)-1-(methoxymethyl)-4-oxoazetidin-2-yl]acrylaldehydeand triphenylphosphineoxide in a ratio of about 1:1 (3.7 g).

Production Example 39

A mixture of 5-[(cyclobutylmethyl) sulfonyl]-1-phenyl-1H-tetrazole (2.04g) and THF (40 ml) was cooled to −78° C., potassium hexamethyldisilazide(1.0 M THF solution, 8.4 ml) was added thereto and the mixture wasstirred for 30 minutes. A solution of(2R,3R)-3-(methoxymethoxy)-1-(4-methoxyphenyl)-4-oxoazetidine-2-carbaldehyde(1.85 g) in THF (30 ml) was added to the resulting reaction mixture andthe mixture was stirred at the same temperature for 30 minutes. Theresulting reaction mixture was allowed to warm up to room temperature. Asaturated aqueous ammonium chloride solution was added to the mixtureand the mixture was extracted with AcOEt. The obtained organic layer waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate. The organic layer was concentrated underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (hexane/AcOEt) to give(3R)-4-(2-cyclobutylvinyl)-3-(methoxymethoxy)-1-(4-methoxyphenyl)azetidin-2-one(1.25 g) as an oily product.

Production Example 40

(1,5-Cyclooctadiene)(pyridine)(tricyclohexylphosphine) iridium (I)hexafluorophosphate (270 mg) was added to a mixture of(3R)-4-(2-cyclobutylvinyl)-3-(methoxymethoxy)-1-(4-methoxyphenyl)azetidin-2-one(1.06 g) and CH₂Cl₂ (24 ml) and the mixture was stirred at roomtemperature overnight under hydrogen atmosphere. The resulting reactionmixture was concentrated under reduced pressure and the resultingresidue was purified by silica gel column chromatography (hexane/AcOEt)to give(3R,4S)-4-(2-cyclobutylethyl)-3-(methoxymethoxy)-1-(4-methoxyphenyl)azetidin-2-one(960 mg) as an oily product.

Production Example 41

A mixture of 4-methylpentanal (1.1 g),(2R,5R)-2,5-dimethylpyrrolidine-1-amine (1.29 g), CH₂Cl₂ (21.9 ml) andanhydrous magnesium sulfate (3.97 g) was stirred at room temperature for2 hours. Insoluble material was removed by filtration from the resultingreaction mixture and the filtrate was concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/AcOEt) to give(2R,5R)-2,5-dimethyl-N-[(1E)-4-methylpentylidene]pyrrolidin-1-amine(1.63 g) as an oily product.

Production Example 42

1-Chloro-N,N,2-trimethylpropenylamine (5.7 g) was added at roomtemperature to a mixture of (methoxymethoxy)acetic acid (5.13 g) andtoluene (105 ml) and the mixture was stirred at room temperature for 1hour under nitrogen atmosphere (mixture A). A mixture of(2R,5R)—N-[(E)-(4-bromophenyl)methylene]-2,5-dimethylpyrrolidin-1-amine(3.0 g), Et₃N (11.9 ml) and toluene (51 ml) was stirred at 100° C. whilethe mixture A was added dropwise thereto over a period of 30 minutes.The resulting reaction mixture was stirred at 100° C. for 5 hours. Waterwas added to the resulting reaction mixture and the mixture wasextracted with AcOEt. The obtained organic layer was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureand the resulting residue was purified by silica gel columnchromatography (hexane/AcOEt) to give(3R,4S)-4-(4-bromophenyl)-1-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-3-(methoxymethoxy)azetidin-2-one(3.1 g) as a solid.

Production Example 43

A mixture of(3R,4S)-3-(benzyloxy)-1-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-4-β-methylbutyl)azetidin-2-one(470 mg), MeOH (15.5 ml) and magnesium monoperoxyphthalate hexahydrate(about 80% purity, 1.3 g) was stirred at room temperature for 2 hours.Water was added to the resulting reaction mixture and the mixture wasextracted with CHCl₃. The obtained organic layer was dried overanhydrous magnesium sulfate and subsequently concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/AcOEt) to give(3R,4S)-3-(benzyloxy)-4-β-methylbutyl)azetidin-2-one (188 mg) as asolid.

Production Example 44

m-Chloroperbenzoic acid (about 25% water content, 555 mg) was addedunder ice-bath cooling to a mixture of2-(2-cyclopropylethyl)furo[3,2-c]pyridine (300 mg) and CHCl₃ (6 ml).After stirring the resulting reaction mixture at room temperature for 8hours, the mixture was cooled with an ice-water bath andm-chloroperbenzoic acid (about 25% water content, 300 mg) was addedagain thereto. The resulting reaction mixture was further stirred atroom temperature for 16 hours. After cooling the resulting reactionmixture with an ice-water bath, a saturated aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium sulfite solution were addedthereto and the mixture was extracted three times with CHCl₃. Theobtained organic layer was dried over anhydrous sodium sulfate andsubsequently concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (CHCl₃/MeOH) to give2-(2-cyclopropylethyl)furo[3,2-c]pyridine 5-oxide (190 mg) as an oilyproduct.

Production Example 45

Under nitrogen atmosphere, CMBP (0.9 ml) was added to a mixture of(3R,4S)-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(500 mg), 4-fluorophenol (350 mg) and toluene (10 ml) and the mixturewas stirred at 150° C. for 1 hour under microwave irradiation. Theresulting reaction mixture was allowed to cool to room temperature, andsubsequently purified by silica gel column chromatography (hexane/AcOEt)to give(3R,4S)-4-[(4-fluorophenoxy)methyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one (620 mg) as an oily product.

Production Example 46

Under nitrogen atmosphere, CMMP (120 mg) was added to a mixture of(3R,4S)-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(200 mg), pyrimidin-2-ol (100 mg) and toluene (2 ml) and the mixture wasstirred at 130° C. for 1 hour under microwave irradiation. The resultingreaction mixture was allowed to cool to room temperature andsubsequently concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-[(pyrimidin-2-yloxy)methyl]azetidin-2-one(120 mg) as an oily product.

Production Example 47

A mixture of(3R,4S)-4-(4-bromophenyl)-3-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(250 mg), sodium cyclopropanesulfinate (185 mg), CuI (138 mg),N,N′-dimethylethylenediamine (0.155 ml) and DMF (5 ml) was stirred at130° C. for 1 hour under microwave irradiation. Water was added to theresulting reaction mixture and the mixture was extracted twice withAcOEt. The obtained organic layer was washed with a saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate and thesolvent was distilled off under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-3-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-4-[4-(cyclopropylsulphonyl)phenyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(246 mg) as an oily product.

Production Example 48

Under argon atmosphere, a mixture of(3R,4S)-4-(4-bromophenyl)-3-([4-(cyclohexyloxy)pyridin-2-yl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(300 mg), Pd(OAc)₂ (13 mg), cesium carbonate (565 mg),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (54 mg),potassium trifluoro(methoxymethyl)borate (263 mg), toluene (6 ml) andwater (1.3 ml) was stirred at 100° C. overnight. Pd(OAc)₂ (13 mg),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (54 mg) andpotassium trifluoro(methoxymethyl)borate (263 mg) were added to theresulting reaction mixture and the mixture was stirred at 100° C.overnight under argon atmosphere. Water was added to the resultingreaction mixture and the mixture was extracted twice with AcOEt. Theobtained organic layer was washed with a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure. The resulting residuewas purified by amino-silica gel column chromatography (hexane/AcOEt) togive(3R,4S)-3-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)-4-[4-(methoxymethyl)phenyl]azetidin-2-one(101 mg) as an oily product.

Production Example 49

A mixture of(3R,4S)-3-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(200 mg), Ag₂O (360 mg), benzyl bromide (0.19 ml), tetra-n-butylammoniumiodide (18 mg) and CH₂Cl₂ (2 ml) was stirred at room temperatureovernight. Ag₂O (600 mg) and benzyl bromide (0.3 ml) were added to theresulting reaction mixture and the mixture was stirred at roomtemperature for 2 days. The resulting reaction mixture was filtered andthe filtrate was concentrated under reduced pressure. The resultingresidue is purified by silica gel column chromatography (hexane/AcOEt)to give(3R,4S)-4-[(benzyloxy)methyl]-3-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(94 mg) as an oily product.

Production Example 50

Under argon atmosphere, a mixture of(3R,4S)-4-[(hex-5-en-1-yloxy)methyl]-3-{[4-(hex-5-en-1-yloxy)pyridin-2-yl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(340 mg),dichloro[1,3-bis(mesityl)imidazolidin-2-ylidene](benzylidene)(tricyclohexylphosphoranylidene)ruthenium(VIII) (60 mg) and CH₂Cl₂ (170 ml) was stirred at room temperatureovernight. The resulting reaction mixture was concentrated under reducedpressure and the resulting residue was purified by silica gel columnchromatography (hexane/AcOEt) to give(3R,6S)-3-(methoxymethoxy)-5-(methoxymethyl)-8,19-dioxa-5,23-diazatricyclo[18.3.1.0^(˜)3,6^(˜)]tetracosa-1(24),13,20,22-tetraen-4-one (148 mg) as an oily product.

Production Example 51

A mixture of(3R,4S)-4-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxyethyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(4 g), THF (50 ml) and 1,1′-thiocarbonyldiimidazole (6.2 g) was stirredat 80° C. overnight. The resulting reaction mixture was allowed to coolto room temperature and subsequently concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/AcOEt) to giveO-{(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-[(2S,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-4-oxoazetidin-2-yl]ethyl1H-imidazol-1-carbothioate (5.2 g) as an oily product.

Production Example 52

Under argon atmosphere, a mixture ofO-{(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-[(2S,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-4-oxoazetidin-2-yl]ethyl)1H-imidazol-1-carbothioate (5.2 g), benzene (26 ml) and tri-n-butyltinhydride (6.2 ml) was stirred at 100° C. for 5 minutes. 2,2′-Azobis(isobutyronitrile) (500 mg) was added to the resulting reaction mixtureand the mixture was stirred at 100° C. for 2 hours. The resultingreaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(3 g) as an oily product.

Production Example 53

Under nitrogen atmosphere, a mixture of1H-imidazo[4,5-c]pyridine-6-methyl carboxylate (1 g),2-cyclohexylethanol (2 ml), CMBP (2 ml) and toluene (10 ml) was stirredat 90° C. overnight. The resulting reaction mixture was concentratedunder reduced pressure and purified by silica gel column chromatography(hexane/AcOEt) to give (1)1-(2-cyclohexylethyl)-1H-imidazo[4,5-c]pyridine-6-methyl carboxylate(640 mg) and (2)3-(2-cyclohexylethyl)-3H-imidazo[4,5-c]pyridine-6-methyl carboxylate(450 mg) each as an oily product.

Production Example 54

1-Hexyl-1H-pyrrolo[3,2-c]pyridin-6-carbonitrile (367 mg) was prepared asa foamy solid from 6-chloro-1-hexyl-1H-pyrrolo[3,2-c]pyridine (700 mg)in the same manner as in the method described in Example 11.

Production Example 55

A mixture of sodium hydrogen carbonate (218 mg) and water (13 ml) wasadded to a mixture of6-(chloromethyl)-1-(2-cyclohexylethyl)-1H-imidazo[4,5-c]pyridinehydrochloride (320 mg) and CH₂Cl₂ (13 ml) and the mixture was stirred atroom temperature for 5 minutes. The organic layer and the aqueous layerof the resulting reaction mixture were separated and the aqueous layerwas extracted with CH₂Cl₂. The obtained organic layers were combined andwashed with a saturated aqueous sodium chloride solution. The obtainedorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Acetone (13 ml) and sodium iodide(800 mg) were added to the resulting residue and the mixture was stirredat room temperature for 3 hours under nitrogen atmosphere. After addingTHF (13 ml) and toluene (30 ml) to the resulting reaction mixture, themixture was concentrated under reduced pressure to about 2 ml. Insolublematerial was removed by filtration from the obtained mixture and toluene(30 ml) was added again to the filtrate The reaction mixture wasconcentrated under reduced pressure to about 1 ml (mixture A).

Under argon atmosphere, a mixture of tert-butyl((1S)-1-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(261 mg) and THF (5 ml) was cooled to −78° C. with stirring, LDA (1.12 Mhexane-THF solution, 2.5 ml) was added dropwise and the mixture wasstirred at the same temperature for 30 minutes. The mixture A was addeddropwise at −78° C. to the resulting reaction mixture under argonatmosphere and the mixture was stirred at the same temperature for 1hour. The resulting reaction mixture was allowed to warm up to roomtemperature, a saturated aqueous ammonium chloride solution and AcOEtwere added thereto. The organic layer and the aqueous layer wereseparated and the aqueous layer was extracted with AcOEt. The obtainedorganic layers were combined and washed with a saturated aqueous sodiumchloride solution. The obtained mixture was dried over anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/AcOEt) to give tert-butyl{(1S)-1-[(4R)-4-{[1-(2-cyclohexylethyl)-1H-imidazo[4,5-c]piridin-6-yl]methyl}-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(150 mg) as an oily product.

Production Example 56

Under nitrogen atmosphere, a mixture of 1-oxaspiro[4.5]decan-8-one (500mg) and CH₂Cl₂ (5 ml) was cooled with a dry ice-acetone bath anddiisobutylaluminium hydride (1.04 M hexane solution, 3.5 ml) was slowlyadded thereto. The reaction mixture was stirred for 10 minutes whilecooled in the dry ice-acetone bath and subsequently MeOH and sodiumsulfate decahydrate were added thereto. The obtained mixture was allowedto warm up to room temperature and stirred for 6 hours. Anhydrous sodiumsulfate was added thereto and the mixture was further stirred for 14hours. The obtained mixture was filtered through Celite and the filtratewas concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (hexane/AcOEt) to give anoily product (258 mg). The obtained oily product (144 mg) was dissolvedin toluene (4 ml) and 4-methoxybenzoic acid (210 mg),tri-n-butylphosphine (0.34 ml) and(E)-N,N,N′,N′-tetramethyldiazene-1,2-dicarboxamide (238 mg) were addedthereto under ice-bath cooling. The mixture was stirred for 10 minutesunder ice-bath cooling and subsequently stirred at 60° C. for 24 hours.The obtained mixture was allowed to cool to room temperature. Insolublematerial was removed by filtration and the filtrate was concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane/AcOEt) to give (1)(5s,8r)-1-oxaspiro[4.5]deca-8-yl 4-methoxybenzoate (20.7 mg) and (2)(5r,8s)-1-oxaspiro[4.5]deca-8-yl 4-methoxybenzoate (182 mg) each as anoily product.

Production Example 57

A solution of tert-butyl((1S)-1-[(4R)-4-{[2-(2-cyclopropylethyl)furo[3,2-c]pyridin-4-yl]methyl}-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(75 mg) in EtOH (3 ml) was subjected to a reaction with acontinuous-flow hydrogenation reactor (H-Cube Pro (registeredtradename); manufactured by ThalesNano) and CatCart (registeredtradename) 10% Pd/C (manufactured by ThalesNano, 70×4 mm) as a cartridgecatalyst under the conditions of a flow rate of 1.0 ml/min, a pressureof 1 bar and a temperature of 25° C. The resulting reaction mixture wasconcentrated under reduced pressure, and a solution of the residue inEtOH (3 ml) was subjected to a reaction again with a continuous-flowhydrogenation reactor (H-Cube Pro (registered tradename); manufacturedby ThalesNano) and CatCart (registered tradename) 10% Pd/C (manufacturedby ThalesNano, 70×4 mm) as a cartridge catalyst under the conditions ofa flow rate of 1.0 ml/min, a pressure of 50 bar and a temperature of 60°C. The resulting reaction mixture was concentrated under reducedpressure, and a solution of the residue in EtOH (3 ml) was subjected toa reaction again with a continuous-flow hydrogenation reactor (H-CubePro (registered tradename); manufactured by ThalesNano) and CatCart(registered tradename) 10% Pd/C (manufactured by ThalesNano, 70×4 mm) asa cartridge catalyst under the conditions of a flow rate of 1.0 ml/min,a pressure of 50 bar and a temperature of 60° C. The resulting reactionmixture was concentrated under reduced pressure to give tert-butyl ((1S)-1-[(4R)-4-{[2-(2-cyclopropylethyl)-2,3-dihydrofuro[3,2-c]pyridin-4-yl]methyl}-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(65.7 mg) as an oily product.

Production Example 58

1 M Aqueous sodium hydroxide solution (2 ml) was added to a mixture of(5r,8s)-1-oxaspiro[4.5]deca-8-yl 4-methoxybenzoate (175 mg), MeOH (1 ml)and THF (2 ml) and the mixture was stirred at 50° C. for 16 hours. Theresulting reaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure. The resulting residue was extractedwith diethyl ether. The organic layer was washed with a saturatedaqueous sodium hydrogen carbonate solution and a saturated aqueoussodium chloride solution, subsequently dried over anhydrous magnesiumsulfate and concentrated under reduced pressure (residue A). The aqueouslayer was extracted three times with AcOEt, the organic layer was driedover anhydrous magnesium sulfate and concentrated under reduced pressure(residue B). The residue B was purified by amino-silica gel columnchromatography (hexane/AcOEt). The obtained compound was mixed with theresidue A to give (5r,8s)-1-oxaspiro[4.5]decan-8-ol (79.6 mg) as an oilyproduct.

Production Example 59

A mixture of {4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methanol (5g) and CH₂Cl₂ (18 ml) was cooled with an ice-water bath. PBr₃ (0.43 ml)was added and the mixture was stirred at room temperature for 2 hours.After cooling the resulting reaction mixture with an ice-water bath, asaturated aqueous sodium hydrogen carbonate solution was added theretoand the mixture was stirred at room temperature for 30 minutes. CHCl₃and a saturated aqueous sodium chloride solution were added to thereaction mixture. The organic layer was separated, dried over anhydrousmagnesium sulfate and subsequently concentrated under reduced pressure.Toluene (5 ml) was added to the resulting residue (mixture A).

A mixture of tert-butyl{(1R)-1-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(1.13 g) and THF (18 ml) was cooled to −78° C., LDA (1.09 M hexane-THFsolution, 3.5 ml) was added under argon atmosphere and the mixture wasstirred for 30 minutes. Trimethylchlorosilane (0.5 ml) was added to thereaction mixture, and the reaction mixture was allowed to warm up to 0°C. and subsequently stirred for 30 minutes. The resulting reactionmixture was cooled to −78° C. LDA (1.09 M hexane-THF solution, 7 ml) wasadded thereto and the mixture was stirred for 30 minutes. The mixture Awas added to the resulting reaction mixture at −78° C. and the mixturewas stirred for 2 hours. Water was added to the resulting reactionmixture. The reaction mixture was allowed to warm up to room temperatureand extracted with CHCl₃. The obtained organic layer was dried overanhydrous magnesium sulfate and subsequently concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/AcOEt) to give (1) tert-butyl((1R)-1-[(4S)-2,2-dimethyl-4-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(0.97 g) and (2) tert-butyl((1R)-1-[(4R)-2,2-dimethyl-4-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(0.45 g) each as an oily product.

Production Example 60

Hydrogen peroxide (30% aqueous solution, 7 ml) and ammonium molybdatetetrahydrate (2.4 g) were added to a mixture of5-[(2-methoxyethyl)sulfanyl]-1-phenyl-1H-tetrazole (2.33 g) and EtOH (46ml) and the mixture was stirred at 65° C. for 3 hours. The resultingreaction mixture was allowed to cool to room temperature andsubsequently filtered through Celite. After adding water to thefiltrate, the mixture was concentrated under reduced pressure until mostof the EtOH was removed. After adding AcOEt to the residue and themixture was extracted. The organic layer was washed with a saturatedaqueous sodium thiosulfate solution. The obtained organic layer wasdried over anhydrous magnesium sulfate and subsequently concentratedunder reduced pressure. The produced solid was washed using a mixedsolvent of diisopropyl ether-MeOH to give5-[(2-methoxyethyl)sulfonyl]-1-phenyl-1H-tetrazole (2.14 g) as a solid.

Production Example 61

A mixture of (2R,5R)-2,5-dimethyl-N-[(1E)-4-methylpentylidene]pyrrolidin-1-amine (1.62g), Et₃N (9.2 ml) and toluene (48 ml) was heated to 80° C. and benzyloxyacetyl chloride (0.4 M toluene solution, 83 ml) was added thereto withstirring over a period of 4 hours. The reaction mixture was allowed tocool to room temperature, subsequently a saturated aqueous sodiumhydrogen carbonate solution was added thereto and the mixture wasextracted with AcOEt. The obtained organic layer was dried overanhydrous magnesium sulfate and subsequently concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/AcOEt) to give (3R,4S)-3-(benzyloxy)-1-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-4-β-methylbutyl)azetidin-2-one (2.02 g)as an oily product.

Production Example 62

Under nitrogen atmosphere, a mixture of(3R,4S)-4-(4-bromophenyl)-3-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(200 mg), cyclopropylboronic acid (99 mg), Pd(OAc)₂ (17 mg),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (63 mg),tripotassium phosphate (327 mg), toluene (4 ml) and water (0.1 ml) wasstirred at 90° C. for 15 hours. Water was added to the resultingreaction mixture and the mixture was extracted with AcOEt. The obtainedorganic layer was washed with a saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and the solvent wasdistilled off under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-3-[4-(cyclohexyloxy)pyridin-2-yl]methyl}-4-(4-cyclopropylphenyl)-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(126 mg) as an oily product.

Production Example 63

Under nitrogen atmosphere, a mixture of tert-butyl dimethylchlorosilane(2.4 g), imidazole (2.2 g), 4-(dimethylamino)pyridine (140 mg) andCH₂Cl₂ (18 ml) was added under ice-bath cooling to a mixture of(3R,4S)-4-[(1S)-1,2-dihydroxyethyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(3.7 g) and CH₂Cl₂(74 ml) and the mixture was stirred at roomtemperature overnight. Water was added to the resulting reaction mixtureand the mixture was extracted twice with CH₂Cl₂. The obtained organiclayers were combined, washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate. The obtainedorganic layer was concentrated under reduced pressure to give(3R,4S)-4-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxyethyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(4.8 g) as an oily product.

Production Example 64

NaH (60% mineral oil dispersion, 327 mg) was added under ice-bathcooling to a mixture of indan-2-ol (1 g) and DMF (5.04 ml) and themixture was stirred for 1 hour. A mixture of4-chloropyridine-2-carbonitrile (600 mg) and DMF (0.96 ml) was added tothe resulting reaction mixture and the mixture was stirred for 1.5hours. The resulting reaction mixture was poured into ice cooled waterand the mixture was extracted twice with AcOEt. The obtained organiclayers were combined, washed with a saturated aqueous sodium chloridesolution and dried over anhydrous sodium sulfate. The obtained organiclayer was concentrated under reduced pressure, MeOH (20 ml) was added tothe residue and cooled with an ice-water bath, subsequently sodiummethoxide (28% MeOH solution, 0.9 ml) was added thereto and the mixturewas stirred at room temperature for 3 hours. 1 M Hydrochloric acid (14ml) was added to the resulting reaction mixture and the mixture wasstirred at room temperature for 1 hour. The resulting reaction mixturewas concentrated under reduced pressure, a saturated aqueous sodiumhydrogen carbonate solution was added to the residue and the mixture wasextracted with AcOEt. The obtained organic layer was washed with asaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate and subsequently concentrated under reduced pressure. MeOH (20ml) was added to the resulting residue and cooled with an ice-waterbath, subsequently NaBH₄ (720 mg) was added thereto and the mixture wasstirred at room temperature for 15 hours. After cooling the resultingreaction mixture with an ice-water bath, a saturated aqueous sodiumchloride solution was added thereto and the mixture was concentratedunder reduced pressure. Water was added to the resulting residue and themixture was extracted with CHCl₃. The obtained organic layer was driedover anhydrous sodium sulfate and subsequently concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (CHCl₃/MeOH) to give[4-(2,3-dihydro-1H-inden-2-yloxy)pyridin-2-yl]methanol (300 mg) as anoily product.

Production Example 65

CMBP (0.31 ml) was added to a mixture of(3R,4S)-3-[(4-hydroxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(200 mg), 3,3-dimethyl-1-pentanol (141 mg) and toluene (2 ml) and themixture was stirred at 150° C. for 30 minutes under microwaveirradiation. The resulting reaction mixture was allowed to cool to roomtemperature and subsequently concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane/AcOEt) to give(3R,4S)-3-((4-[(3,3-dimethylpentyl)oxy]pyridin-2-yl}methyl)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(123 mg) as an oily product.

Production Example 66

Under nitrogen atmosphere, CMMP (100 mg) was added to a mixture of(3R,4S)-3-[(4-hydroxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(200 mg), (S)-4-methyl-2-pentanol (0.11 ml) and toluene (2 ml) and themixture was stirred at 100° C. for 1 hour under microwave irradiation.The resulting reaction mixture was allowed to cool to room temperatureand subsequently concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane/AcOEt)to give(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)-3-[(4-{[(2R)-4-methylpentan-2-yl]oxy)pyridin-2-yl}methyl)azetidin-2-one (131 mg) as an oily product.

Production Example 67

Under nitrogen atmosphere, trimethylsilylcyanide (0.183 ml) was added toa mixture of 2-(2-cyclopropylethyl)furo[3,2-c]pyridine 5-oxide (190 mg),Et₃N (0.33 ml) and MeCN (4 ml) and the mixture was stirred at 85° C. for16 hours. After cooling the resulting reaction mixture to roomtemperature, Et₃N (0.65 ml) and trimethylsilylcyanide (0.35 ml) wereadded thereto. The reaction mixture was stirred again at 85° C. for 3.5hours and subsequently allowed to cool to room temperature. AcOEt wasadded to the resulting reaction mixture and washed sequentially with asaturated aqueous sodium hydrogen carbonate solution and a saturatedaqueous sodium chloride solution. The obtained organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/AcOEt) to give2-(2-cyclopropylethyl)furo[3,2-c]pyridine-4-carbonitrile (148 mg) as anoily product.

Production Example 68

Under nitrogen atmosphere, sodium iodide (6.8 g), which was dried inadvance at 30° C. for 7 hours and at room temperature for 5 days underreduced pressure, was added to a mixture of4-chloro-2-(chloromethyl)pyridine (7 g) and THF (100 ml) and the mixturewas stirred at room temperature for 4 hours. Anhydrous sodium sulfate(dried at 50° C. for 4 hours under reduced pressure, 3 g) was added tothe reaction mixture and the mixture was further stirred for 30 minutes(mixture A).

Under nitrogen atmosphere, to a solution of(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one (5g) in THF (50 ml), LDA (1.12 M hexane-THF solution, 25 ml) was slowlyadded at −78° C. The reaction mixture was stirred at −78° C. for 30minutes, subsequently the mixture A was added dropwise thereto and themixture was further stirred for 30 minutes. A saturated aqueous ammoniumchloride solution was added to the resulting reaction mixture,subsequently the mixture was allowed to warm up to room temperature andextracted twice with AcOEt. The obtained organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane/AcOEt) to give(3R,4S)-3-[(4-chloropyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(5.32 g) as an oily product.

Production Example 69

PBr₃ (0.1 ml) was added to a mixture of(1-hexyl-1H-pyrrolo[3,2-c]pyridin-6-yl)methanol (220 mg) and CH₂Cl₂ (5ml) under ice-bath cooling, subsequently allowed to warm up to roomtemperature and the mixture was stirred for 2 hours. The resultingreaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and the mixture was stirred for 1 hour. The obtainedmixture was filtered through Celite and the Celite pad was washed withtoluene. The organic layer was separated from the obtained filtrate andwashed with a saturated aqueous sodium chloride solution. The obtainedorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to about 2 ml (mixture A).

Under nitrogen atmosphere, a mixture of(3R,4S)-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(200 mg) and THF (2 ml) was cooled with a dry ice-acetone bath, LDA(1.09 M hexane-THF solution, 1 ml) was added and the mixture was stirredfor 30 minutes. The mixture A was slowly added to the reaction mixture,subsequently the mixture was stirred for 30 minutes under dryice-acetone bath cooling. A saturated aqueous ammonium chloride solutionwas added to the resulting reaction mixture, and the mixture was allowedto warm up to room temperature and extracted with AcOEt. The obtainedorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (CHCl₃/MeOH) to give(3R,4S)-3-[(1-hexyl-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(324 m g) as an oily product.

Production Example 70

10% Pd/C (50% water content, 1.5 g) was added to a mixture of(3R,4S)-3-{[4-(benzyloxy)-5-methylpyridin-2-yl]methyl}-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(3.46 g) and MeOH (150 ml) and the mixture was stirred at roomtemperature for 2 hours under hydrogen atmosphere of 4 atm. The reactionmixture was filtered through Celite and the filtrate was concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (CHCl₃/MeOH) to give(3R,4S)-3-[(4-hydroxy-5-methylpyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(1.82 g) as a foamy solid.

Production Example 71

Under nitrogen atmosphere, a mixture of(3R,4S)-4-(4-bromophenyl)-3-({[4-(cyclohexyloxy)pyridin-2-yl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(200 mg), morpholine (0.066 ml),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (37 mg),tripotassium phosphate (163 mg), bis(dibenzylideneacetone)palladium (11mg) and toluene (2 ml) was stirred at 100° C. overnight. Water was addedto the resulting reaction mixture and the mixture was extracted withAcOEt. The obtained organic layer was washed with a saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate and thesolvent was distilled off under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-3-({[4-(cyclohexyloxy)pyridin-2-yl]methyl}-3-(methoxymethoxy)-1-(methoxymethyl)-4-[4-(morpholin-4-yl)phenyl]azetidin-2-one(138 mg) as an oily product.

Production Example 72

Under argon atmosphere, a mixture of(3R,4S)-3-[(5-bromo-4-methoxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(125 mg), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.13 ml),bis(tricyclohexylphosphine)palladium (II) dichloride (44 mg),tripotassium phosphate (125 mg), DOX (2.5 ml) and water (0.35 ml) wasstirred at 90° C. overnight. The resulting reaction mixture was allowedto cool to room temperature and subsequently a saturated aqueous sodiumhydrogen carbonate solution was added thereto. The obtained mixture wasextracted with AcOEt and the organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane/AcOEt)to give(3R,4S)-3-[(5-benzyl-4-methoxypyridin-2-yl)methyl]-4-isobutyl-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(27 mg) as an oily product.

Production Example 73

A mixture of(3R,4S)-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(530 mg), cyclopropylmethyliodide (8.39 g) and Ag₂O (3 g) was stirred at90° C. overnight. Ag₂O (3 g) was added to the resulting reaction mixtureand the mixture was further stirred at 90° C. overnight. Insolublematerial was removed by filtration from the resulting reaction mixtureand the obtained filtrate was concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane/AcOEt) to give(3R,4S)-4-[(but-3-en-1-yloxy)methyl]-3-(methoxymethoxy)-1-(methoxymethyl)-3-((4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(84.6 mg) as an oily product.

Production Example 74

Under nitrogen atmosphere, a mixture of trimethylsilylacetylene (320 mg)and THF (1.6 ml) was cooled at −78° C. and n-butyl lithium (1.58 Mhexane solution, 2.6 ml) was added dropwise. The resulting reactionmixture was stirred for 10 minutes under ice-bath cooling andsubsequently cooled again to −78° C.N,N,N′,N′,N″,N″-Hexamethylphosphoric acid triamide (0.86 ml) was addedto the resulting reaction mixture, and the mixture was stirred at thesame temperature for 30 minutes and subsequently(2-bromoethyl)cyclopropane (500 mg) was added thereto. The resultingreaction mixture was allowed to warm up to room temperature and stirredovernight. Water was added to the resulting reaction mixture and theorganic layer was separated. The obtained organic layer was washed threetimes with water and twice with a saturated aqueous sodium chloridesolution. The obtained organic layer was dried over anhydrous sodiumsulfate and subsequently concentrated under reduced pressure to give(4-cyclopropylbut-1-yn-1-yl)(trimethyl)silane (506 mg) as an oilyproduct.

Production Example 75

Under argon atmosphere, tetra-n-butylammonium fluoride (1 M THFsolution, 8.8 ml) was added to a mixture of 3-bromopyridin-4(1H)-one(500 mg), (4-cyclopropylbut-1-yn-1-yl)(trimethyl)silane (1.44 g), Et₃N(2.8 ml) and DMF (5 ml). The obtained mixture was irradiated withsupersonic wave for 30 seconds, subsequentlybis(triphenylphosphine)palladium (II) dichloride (420 mg) was addedthereto and the mixture was stirred at 110° C. for 1 hour undermicrowave irradiation. AcOEt and silica gel were added to the resultingreaction mixture and the mixture was concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/AcOEt) to give2-(2-cyclopropylethyl)furo[3,2-c]pyridine (302 mg) as an oily product.

Production Examples 76 to 194

Production Example compounds shown in Tables to be described later wereproduced in the same manner as in the method described in the aboveProduction Examples.

Production Example 195

A mixture of(3R,4S)-3-(methoxymethoxy)-4-(3,3,3-trifluoropropyl)azetidin-2-one (628mg), 1,2-dichloroethane (20 ml), chloro(methoxy)methane (1.5 ml) andDIPEA (3.5 ml) was stirred at 90° C. for 12 hours. The resultingreaction mixture was allowed to cool to room temperature. A saturatedaqueous sodium hydrogen carbonate solution was added thereto and themixture was extracted with AcOEt. The obtained organic layer was washedwith a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate. The organic layer was concentrated underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (hexane/AcOEt) to give (1)(3R,4S)-3-(methoxymethoxy)-1-(methoxymethyl)-4-(3,3,3-trifluoropropyl)azetidin-2-one(129 mg) as a solid, and (2)(3R,4S)-3-(methoxymethoxy)-1-[(methoxymethoxy)methyl]-4-(3,3,3-trifluoropropyl)azetidin-2-one(474 mg) as an oily product.

Production Example 196

Under argon atmosphere, a mixture of tert-butyl[(1S)-1-{(4R)-4-[(4-chloropyridin-2-yl)methyl]-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl}-3-methylbutyl]carbamate(1.03 g), 2-(tri methylsilyl)ethanethiol (0.4 ml),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (700 mg),tris(dibenzylideneacetone)dipalladium (550 mg), DIPEA (0.85 ml) and DOX(16 ml) was stirred at 120° C. for 2 hours under microwave irradiation.After cooling the resulting reaction mixture to room temperature, AcOEtwas added thereto, and the insoluble materials were removed byfiltration. The filtrate was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography (hexane/AcOEt)to give tert-butyl[(1S)-1-{(4R)-2,2-dimethyl-5-oxo-4-[(4-{[2-(trimethylsilyl)ethyl]sulfanyl}pyridin-2-yl)methyl]-1,3-dioxolan-4-yl}-3-methylbutyl]carbamate(1.1 g) as a foamy solid.

Production Example 197

Under nitrogen atmosphere, 2,2,6,6-tetramethylpiperidinyl-magnesiumchloride-lithium chloride complex (1 M THF-toluene solution, 91 ml) wasadded dropwise at −20° C. over a period of 2 hours to a mixture ofmethyl N-(tert-butoxycarbonyl)-O-(2-cyclopropylethyl)-L-serinate (6.5g), dibromomethane (8.0 g) and THF (22 ml) while maintaining an internaltemperature below −11° C. and subsequently stirred at −15° C. for 2hours. The resulting reaction mixture was poured into a cold mixture of5% aqueous citric acid solution and AcOEt (cooled with ice-water bath)and subsequently stirred for 10 minutes. The organic layer wasseparated, and washed with 5% aqueous citric acid solution 3 times and asaturated aqueous sodium chloride solution. The obtained organic layerwas dried over anhydrous sodium sulfate, and subsequently concentratedunder reduced pressure to give the residue (10.7 g) containingtert-butyl[(2S)-4,4-dibromo-1-(2-cyclopropylethoxy)-3-oxobutan-2-yl]carbamate asan oily product.

Production Example 198

2 M Aqueous sodium hydroxide solution (57 ml) was added dropwise underice-bath cooling to a mixture of tert-butyl[(2S)-4,4-dibromo-1-(2-cyclopropylethoxy)-3-oxobutan-2-yl]carbamate (9.6g) and toluene (76 ml) over a period of 15 minutes and the mixture wassubsequently stirred at room temperature for 2 hours. Toluene and waterwere added to the resulting reaction mixture and subsequently theorganic layer and the aqueous layer were separated. The organic layerwas extracted twice with water, combined with the aqueous layer obtainedfirst and subsequently AcOEt was added thereto. After cooling theobtained mixture with an ice-water bath, 2 M hydrochloric acid was addedto adjust a pH of the aqueous layer to about 1.5. The organic layer andthe aqueous layer of the resulting reaction mixture were separated andthe aqueous layer was extracted 3 times with AcOEt. The obtained organiclayers were combined and dried over anhydrous sodium sulfate. Theobtained organic layer was concentrated under reduced pressure to give(3S)-3-[(tert-butoxycarbonyl)amino]-4-(2-cyclopropylethoxy)-2-hydroxybutanoicacid (4.53 g) as an oily product.

Production Example 199

Trifluoroacetic acid (12 ml) was added to a solution of ethyl(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpenta-4-enoate (5.7 g) inCH₂Cl₂(40 ml) and the mixture was stirred at room temperature for 1hour. The resulting reaction mixture was concentrated under reducedpressure, THF (60 ml), benzyl chloroformate (3.2 ml), sodium hydrogencarbonate (4.3 g) and water (60 ml) were added to the residue and themixture was stirred at room temperature for 1 hour. The resultingreaction mixture was extracted with AcOEt, the organic layer was washedwith a saturated aqueous sodium chloride solution and subsequently driedover anhydrous magnesium sulfate. The resulting residue was purified bysilica gel column chromatography (hexane/AcOEt) to give ethyl(2S)-2-{[(benzyloxy)carbonyl]amino}-4-methylpenta-4-enoate (4.2 g) as anoily product.

Production Example 200

Under nitrogen atmosphere, a mixture of trifluoroacetic acid (4.5 ml)and CH₂Cl₂ (35 ml) was added dropwise under ice-bath cooling to amixture of diethyl zinc (1.09 M hexane solution, 55 ml) and CH₂Cl₂ (75ml). The resulting reaction mixture was stirred for 30 minutes underice-bath cooling and subsequently diiodomethane (4.8 ml) was addedthereto at the same temperature. After stirring the reaction mixture for30 minutes under ice-bath cooling, a mixture of ethyl(2S)-2-[(benzyloxy) carbonyl]amino}-4-methylpenta-4-enoate (4.2 g) andCH₂Cl₂ (35 ml) was added dropwise at the same temperature. Afterstirring the resulting reaction mixture at room temperature overnight, 1M hydrochloric acid (50 ml) was added under ice-bath cooling. Theobtained mixture was extracted with CHCl₃, the organic layer was washedwith a saturated aqueous sodium hydrogen carbonate solution,subsequently dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane/AcOEt) to give ethylN-[(benzyloxy)carbonyl]-3-(1-methylcyclopropyl)-L-alaninate (3.8 g) asan oily product.

Production Example 201

10% Pd/C (50% water content, 0.95 g) was added to a solution of ethylN-[(benzyloxy)carbonyl]-3-(1-methylcyclopropyl)-L-alaninate (3.8 g) inEtOH (76 ml) and the mixture was stirred at room temperature for 1.5hours under hydrogen atmosphere. Insoluble material was removed byfiltration from the resulting reaction mixture and subsequently thefiltrate was concentrated under reduced pressure. Di-tert-butyldicarbonate (2.85 g) and DIPEA (2.3 ml) were added under ice-bathcooling to a solution of the resulting residue in THF (76 ml) and themixture was stirred at room temperature for 2 hours. The resultingreaction mixture was poured into a saturated aqueous ammonium chloridesolution and the mixture was extracted with AcOEt. The obtained organiclayer was dried over anhydrous sodium sulfate and subsequentlyconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/AcOEt) to give ethylN-(tert-butoxycarbonyl)-3-(1-methylcyclopropyl)-L-alaninate (3.2 g) asan oily product.

Production Example 202

Under nitrogen atmosphere, to a mixture ofN-(tert-butoxycarbonyl)-L-serine (20 g) and DMF (480 ml) was added NaH(60% mineral oil dispersion, 8.6 g) in five portions while maintainingan internal temperature below 5° C. under ice-bath cooling andsubsequently the mixture was stirred for 1 hour under ice-bath cooling.(2-Iodoethyl)cyclopropane (24 g) was added to the resulting reactionmixture and the mixture was stirred at room temperature for 14 hours.After cooling the resulting reaction mixture with an ice-water bath,water and 1 M hydrochloric acid were added to adjust a pH to 2 to 3. Theresulting reaction mixture was extracted three times with AcOEt andsubsequently the organic layer was washed with a saturated aqueoussodium chloride solution. The obtained organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. MeOH(140 ml) and CH₂Cl₂ (420 ml) were added to the resulting residue,(diazomethyl)(trimethyl)silane (2 M hexane solution, 62 ml) was addeddropwise under ice-bath cooling while maintaining an internaltemperature below 6° C. and subsequently the mixture was stirred for 10minutes under ice-bath cooling and at room temperature for 1 hour. AcOHwas added to the resulting reaction mixture to decompose an excessamount of (diazomethyl)(trimethyl)silane and subsequently the reactionmixture was concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/AcOEt) to givemethyl N-(tert-butoxycarbonyl)-O-(2-cyclopropylethyl)-L-serinate (6.51g) as an oily product.

Production Example 203

A mixture of tert-butyl[(1R)-1-[(4R)-2,2-dimethyl-4-((4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-5-oxo-1,3-dioxolan-4-yl]-2-(ethylsulfanyl)ethyl]carbamate(203 mg) and CH₂Cl₂ (4 ml) was cooled with an ice-water bath,subsequently m-chloroperbenzoic acid (about 25% water content, 89.5 mg)was added thereto and the mixture was stirred at the same temperaturefor 1 hour. 10% Aqueous sodium thiosulfate solution was added to theresulting reaction mixture and the mixture was stirred for 10 minutes.After separating the aqueous layer and the organic layer, the organiclayer was washed twice with a saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was dried over anhydrousmagnesium sulfate and subsequently concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(CHCl₃/MeOH) to give tert-butyl[(1R)-1-[(4R)-2,2-dimethyl-4-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-5-oxo-1,3-dioxolan-4-yl]-2-ethylsulfinyl)ethyl]carbamate(172 mg) as a solid.

Production Example 204

A mixture of tert-butyl[(1R)-1-[(4R)-2,2-dimethyl-4-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-5-oxo-1,3-dioxolan-4-yl]-2-ethylsulfanyl)ethyl]carbamate(103 mg) and CH₂Cl₂ (6 ml) was cooled with an ice-water bath,subsequently m-chloroperbenzoic acid (about 25% water content, 91 mg)was added thereto and the mixture was stirred at the same temperaturefor 1 hour and then at room temperature for 1 hour. The resultingreaction mixture was cooled again with an ice-water bath,m-chloroperbenzoic acid (about 25% water content, 9 mg) was addedthereto and the mixture was stirred at room temperature for 30 minutes.10% Aqueous sodium thiosulfate solution was added to the resultingreaction mixture and the mixture was stirred for 10 minutes. Afterseparating the aqueous layer and the organic layer, the organic layerwas washed twice with a saturated aqueous sodium hydrogen carbonatesolution. The obtained organic layer was dried over anhydrous magnesiumsulfate and subsequently concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(CHCl₃/AcOEt) to give tert-butyl[(1R)-1-[(4R)-2,2-dimethyl-4-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-5-oxo-1,3-dioxolan-4-yl]-2-(ethylsulfonyl)ethyl]carbamate (81 mg) as a solid.

Production Example 205

A mixture of[(2S,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-3-((4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-oxoazetidin-2-yl]methylmethanesulfonate (1.19 g), DMF (25 ml) and potassium thioacetate (560mg) was stirred at 60° C. overnight. Water was added to the resultingreaction mixture and the mixture was extracted with AcOEt. The obtainedorganic layer was washed sequentially with a saturated aqueous sodiumhydrogen carbonate solution and a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate. The obtainedorganic layer was concentrated under reduced pressure and the residuewas purified by silica gel column chromatography (hexane/AcOEt) to giveS-{[(2R,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-oxoazetidin-2-yl]methyl})thioacetate (700 mg) as an oily product.

Production Example 206

A saturated aqueous sodium hydrogen carbonate solution was added to amixture of 2-(bromomethyl)-4-[(trans-4-methylcyclohexyl)oxy]pyridinehydrobromate (766 mg) and CH₂Cl₂ (25 ml) and the mixture was stirred atroom temperature for 10 minutes. After separating the organic layer fromthe obtained mixture, the aqueous layer was extracted with CH₂Cl₂. Theobtained organic layers were combined, dried over anhydrous magnesiumsulfate and diluted with toluene. The obtained mixture was concentratedunder reduced pressure to about 20 ml. Toluene was added again to theobtained mixture and the mixture was concentrated to about 10 ml(mixture A).

Under nitrogen atmosphere, LDA (1.09 M hexane-THF solution, 2.2 ml) wasslowly added at −78° C. with stirring to a mixture of(3R,4R)-4-[(ethylsulfanyl)methyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(407 mg) and THF (6 ml). The resulting reaction mixture was stirred atthe same temperature for 30 minutes and subsequently the mixture A wasadded dropwise thereto. After stirring at the same temperature for 1.5hours, a saturated aqueous ammonium chloride solution was added theretoand the mixture was allowed to warm up to room temperature. The obtainedmixture was extracted with AcOEt. The obtained organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (CHCl₃/AcOEt) and subsequently purified again with silicagel column chromatography (hexane/AcOEt) to give(3R,4R)-4-[(ethylsulfanyl)methyl]-3-(methoxymethoxy)-1-(methoxymethyl)-3-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)azetidin-2-one(599 mg) as an oily product.

Production Example 207

Under argon atmosphere, tetra-n-butylammonium fluoride (1 M THFsolution, 1.2 ml) was added to a mixture of 2-ethylhexyl3-[(3-bromo-2-cyanopyridin-4-yl)sulfanyl}propanoate (200 mg),(4-cyclopropylbut-1-yn-1-yl)(trimethyl)silane (170 mg), Et₃N (0.49 ml)and DMF (1.5 ml). The obtained mixture was irradiated with supersonicwave for 30 seconds, subsequently bis(triphenylphosphine)palladium (11)dichloride (70 mg) was added thereto and the mixture was stirred at 110°C. for 30 minutes under microwave irradiation. AcOEt was added to theresulting reaction mixture and the mixture was washed with a saturatedaqueous sodium chloride solution. The obtained organic layer was driedover anhydrous magnesium sulfate and subsequently concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane/AcOEt) to give2-(2-cyclopropylethyl)thieno[3,2-c]pyridin-4-carbonitrile (12 mg) as anoily product.

Production Example 208

2-Ethylhexyl 3-sulfanylpropanoate (2.4 ml) was added under ice-bathcooling to a mixture of 3-bromo-4-chloropyridin-2-carbonitrile (2 g),Et₃N (2.6 ml) and DMF (20 ml) and the mixture was stirred at the sametemperature for 10 minutes and then at room temperature for 11 hours.Water and AcOEt were added to the resulting reaction mixture and theorganic layer was separated. The obtained organic layer was washed witha saturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The obtained organic layer was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (hexane/AcOEt) to give 2-ethylhexyl3-[(3-bromo-2-cyanopyridin-4-yl)sulfanyl]propanoate (2.7 g) as an oilyproduct.

Production Example 209

Hydrogen fluoride-pyridine (25 g) was cooled to −10° C. (MeOH-ice bath)and ethyl (2S)-2-amino-4-methylpenta-4-enoate mono{[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hepta-1-yl]methanesulfonicacid} salt (7.5 g) was slowly added so that an internal temperature waskept below −5° C. The resulting reaction mixture was stirred at roomtemperature for 3 hours, subsequently cooled again in the MeOH-ice bathand a saturated aqueous ammonium acetate solution was added thereto.Subsequently, 28% aqueous ammonia solution was added to adjust a pH ofthe reaction mixture to about 9.5. The obtained mixture was extractedthree times with methyl-tert-butyl ether. The obtained organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure. THF (50 ml) was added to the resulting residue, DIPEA (3.3 ml)and di-tert-butyl dicarbonate (3.86 ml) were added thereto at roomtemperature and the mixture was stirred for 4 hours. The resultingreaction mixture was concentrated under reduced pressure and water wasadded to the residue and the mixture was extracted with AcOEt. Theorganic layer was dried over anhydrous magnesium sulfate andsubsequently concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/AcOEt) to giveethyl N-(tert-butoxycarbonyl)-4-fluoro-L-leucinate (2.65 g) as an oilyproduct.

Production Example 210

PtO₂ (61 mg) was added to a solution of(3R)-4-(2-cyclopropylvinyl)-3-(methoxymethoxy)-1-(4-methoxyphenyl)azetidin-2-one(831 mg) in toluene (25 ml) and the mixture was stirred at 0° C. for 6hours under hydrogen atmosphere. Insoluble material was removed byfiltration from the resulting reaction mixture and subsequently thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/AcOEt) to give(3R,4S)-4-(2-cyclopropylethyl)-3-(methoxymethoxy)-1-(4-methoxyphenyl)azetidin-2-one(574 mg) as an oily product.

Production Example 211

Under nitrogen atmosphere, diisopropyl azodicarboxylate (1.2 ml) wasadded dropwise under ice-bath cooling to a mixture of(3R,4S)-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(300 mg), THF (12 ml), thioacetic acid (0.32 ml) and triphenyl phosphine(1.6 g) and the mixture was stirred at room temperature overnight. Waterwas added to the resulting reaction mixture and the mixture wasextracted with CHCl₃. The obtained organic layer was dried overanhydrous magnesium sulfate and subsequently concentrated under reducedpressure. Diisopropyl ether was added to the resulting residue, and theinsoluble materials were removed by filtration. The obtained filtratewas concentrated under reduced pressure and the residue was purified bysilica gel column chromatography (hexane/AcOEt) to giveS-{[(2R,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-4-oxoazetidin-2-yl]methyl}thioacetate(300 mg) as an oily product.

Production Example 212

1-Bromo-2-methylpropane (0.3 ml) and sodium iodide (435 mg) were addedto a mixture ofS-{[(2R,3R)-3-(methoxymethoxy)-1-(methoxymethyl)-4-oxoazetidin-2-yl]methyl}thioacetate(150 mg), DMF (1.5 ml), MeOH (1.5 ml), and potassium carbonate (420 mg)and the mixture was stirred at 40° C. overnight. Water was added to theresulting reaction mixture and the mixture was extracted with AcOEt. Theobtained organic layer was washed with a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate. Theobtained organic layer was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography (hexane/AcOEt)to give (3R,4R)-4-[(isobutylsulfanyl)methyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one (125mg) as an oily product.

Production Example 213

Methanesulfonyl chloride (2.1 ml) was added under ice-bath cooling to amixture of(3R,4S)-4-(hydroxymethyl)-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(2.7 g), pyridine (4.3 ml) and CH₂Cl₂ (30 ml) and the mixture wasstirred at room temperature for 18 hours. CHCl₃ was added to theresulting reaction mixture and washed sequentially with 0.5 Mhydrochloric acid, a saturated aqueous sodium hydrogen carbonatesolution and a saturated aqueous sodium chloride solution. The obtainedorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/AcOEt) to give a solid (3.4g). Sodium ethanethiolate (575 mg) was added under ice-bath cooling to amixture of the obtained solid (1 g) and DMF (10 ml) and the mixture wasstirred at the same temperature for 1 hour. AcOEt was added to theresulting reaction mixture and the mixture was washed sequentially withwater, a saturated aqueous sodium hydrogen carbonate solution and asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The obtained organic layer was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (hexane/AcOEt) to give(3R,4R)-4-[(ethylsulfanyl)methyl]-3-(methoxymethoxy)-1-(methoxymethyl)azetidin-2-one(300 mg) as an oily product.

Production Examples 214 to 294

Production Example compounds shown in Tables to be described later wereproduced in the same manner as in the method described in the aboveProduction Examples.

Tables to be described later show the structure, physicochemical dataand production method of the Production Example compounds.

Reference Example 1

6 M Hydrochloric acid (1 ml) was added to tert-butyl{(1S)-1-[(4S)-2,2-dimethyl-4-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate (75.2 mg) and the mixture wasstirred at 80° C. overnight. The resulting reaction mixture was allowedto cool to room temperature and subsequently concentrated under reducedpressure. The resulting residue was purified by ODS columnchromatography (MeCN/0.1% aqueous formic acid solution). MeCN and anexcess amount of 1 M hydrochloric acid were added to the obtainedcompound and the solvent was distilled off to give(2S,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoicacid dihydrochloride (50 mg) as a solid.

Reference Example 2

6 M Hydrochloric acid (30 ml) was added to tert-butyl{(1R)-1-[(4S)-2,2-dimethyl-4-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-5-oxo-1,3-dioxolan-4-yl]-3-methylbutyl}carbamate(3.7 g) and the mixture was stirred at 80° C. overnight. After coolingthe resulting reaction mixture with an ice-water bath, 6 M aqueoussodium hydroxide solution was added thereto to adjust a pH of thereaction mixture to about 1.5. The produced insoluble material wascollected by filtration to give(2S,3R)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoicacid hydrochloride (1.2 g) as a solid.

Tables to be described later show the structure and physicochemical dataof Reference Example compounds.

TABLE 5-1 Ex Str 1

2(1)

2(2)

3

4

5

6

7(1)

7(2)

8

9

10 

TABLE 5-2 Ex Str 11

12

13

14

15

16

17 (1)

17 (2)

18

19

20

TABLE 5-3 Ex Str 21

22

23

24

25

26

27

28

29

30

31

32

TABLE 5-4 Ex Str 33

34

35

36

37

38

39

40

41

42

TABLE 5-5 Ex Str 43

44

45

46

47

48

49

50

51

52

53

54

TABLE 5-6 Ex Str 55

56

57

58

59

60

61

62

63

64

TABLE 5-7 Ex Str 65

66

67

68

69

70

71

72

73

74

75

76

TABLE 5-8 Ex Str 77

78

79

80

81

82

83

84

85

86

TABLE 5-9 Ex Str 87

88

89

90

91

92

93

94

95

96

TABLE 5-10 Ex Str  97

 98

 99

100

101

102

TABLE 5-11 Ex Str 103

104

105

106

107

108

109

110

111

112

TABLE 5-12 Ex Str 113

114

115

116

117

118

119

120

TABLE 5-13 Ex Str 121

122

123

124

125

126

127

128

129

130

TABLE 5-14 Ex Str 131

132

133

134

135

136

137

138

139

140

TABLE 5-15 Ex Str 141

142

143

144

145

146

TABLE 6-1 Ex Syn DATA 1 — ESI+: 337.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm:0.09-0.16 (2 H, m), 0.40-0.48 (2 H, m), 0.70 (3 H, d, J = 6.6 Hz),0.75-0.87 (4 H, m), 1.22 (1 H, ddd, J = 14.2, 9.9, 4.0 Hz), 1.37-1.47 (1H, m), 1.63 (2 H, dt, J = 6.6, 6.6 Hz), 1.68-1.82 (1 H, m), 2.83-2.91 (2H, m), 3.11 (1 H, d, J = 13.7 Hz), 4.08 (2 H, t, J = 6.6 Hz), 6.82-6.86(2 H, m), 8.24-8.28 (1 H, m) 2(1) — ESI+: 429.2, 431.2 2(2) — ESI+:411.3 3 — ESI+: 351.2 ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 1.00 (3 H, d, J =6.4 Hz), 1.06 (3 H, d, J = 6.4 Hz), 1.34-1.46 (1 H, m), 1.46-1.58 (2 H,m), 1.58-1.72 (5 H, m), 1.75-1.90 (3 H, m), 1.99-2.13 (2 H, m), 3.27 (1H, d, J = 13.7 Hz), 3.52 (1 H, d, J = 13.7 Hz), 3.62 (1 H, dd, J = 9.2,3.9 Hz), 4.74-4.82 (1 H, m), 7.38 (1 H, d, J = 2.7 Hz), 7.42 (1 H, dd, J= 7.0, 2.7 Hz), 8.50 (1 H, d, J = 7.0 Hz) 4 — ESI+: 377.3 ¹H NMR (400MHz, MeOH-d₄) δ ppm: 0.26-0.36 (4 H, m), 0.85 (3 H, d, J = 6.2 Hz), 0.95(3 H, d, J = 6.2 Hz), 1.31-1.42 (2 H, m), 1.43-1.58 (3 H, m), 1.59-1.80(4 H, m), 1.94-2.05 (2 H, m), 3.04-3.13 (2 H, m), 3.20 (1 H, d, J = 15.0Hz), 4.57-4.66 (1 H, m), 6.89 (1 H, dd, J = 6.1, 2.5 Hz), 6.96 (1 H, d,J = 2.5 Hz), 8.26 (1 H, d, J = 6.1 Hz) 5 — ESI+: 409.3 ¹H NMR (400 MHz,MeOH-d₄) δ ppm: 0.14-0.27 (2 H, m), 0.45-0.60 (2 H, m), 0.90-1.01 (4 H,m), 1.09-1.30 (2 H, m), 1.36-1.56 (3 H, m), 1.81 (2 H, d, J = 13.3 Hz),2.13 (2 H, brs.), 2.39-2.61 (3 H, m), 3.14-3.29 (4 H, m), 4.40-4.51 (1H, m), 6.95 (1 H, dd, J = 6.2, 2.3 Hz), 7.00 (1 H, d, J = 2.2), 8.28 (1H, d, J = 6.3 Hz) 6 — ESI+: 365.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 0.85(3 H, d, J = 6.4 Hz), 0.88-0.97 (6 H, m), 1.01-1.21 (2 H, m), 1.31-1.53(4 H, m), 1.62 (1 H, ddd, J = 14.2, 10.6, 3.2 Hz), 1.70-1.87 (3 H, m),2.03-2.13 (2 H, m), 3.29-3.56 (3 H, m), 4.58-4.75 (1 H, m), 7.33 (1 H,d, J = 2.4 Hz), 7.44 (1 H, dd, J = 6.8, 2.4 Hz), 8.33 (2 H, brs), 8.62(1 H, d, J = 6.8 Hz)

TABLE 6-2 Ex Syn DATA  7(1) — ESI+: 373.3  7(2) — ESI+: 269.2  8 — ESI+:405.3  9 — ESI+: 363.3 ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 0.08-0.21 (2 H,m), 0.41-0.58 (2 H, m), 0.79-0.95 (1 H, m), 1.32-1.51 (2 H, m),1.57-1.73 (5 H, m), 1.79-1.94 (3 H, m), 1.97-2.11 (2 H, m), 2.18-2.34 (1H, m), 2.98-3.07 (1 H, m), 3.13 (1 H, d, J = 13.7 Hz), 3.20 (1 H, d, J =13.7 Hz), 4.10-4.29 (2 H, m), 6.92-6.99 (1 H, m), 6.99-7.06 (1 H, m),8.30 (1 H, d, J = 5.9 Hz) 10 — ESI+: 396.3 11 — ESI+: 426.3 12 — ESI+:381.3 13 — ESI+: 336.1 14 — ESI+: 409.1 15 — ESI+: 377.3 16 — ESI+:405.4 17(1) — ESI+: 365.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 0.69 (3 H, d,J = 6.4 Hz), 0.83 (3 H, d, J = 6.6 Hz), 0.89 (3 H, d, J = 6.6 Hz),1.03-1.17 (2 H, m), 1.22 (1 H, ddd, J = 14.2, 9.9, 3.9 Hz), 1.30-1.47(4H, m), 1.67-1.79 (3 H, m), 2.00-2.09 (2 H, m), 2.82-2.91 (2 H, m),3.09 (1 H, d, J = 13.7 Hz), 4.35 (1 H, dddd, J = 10.6, 10.6, 4.2, 4.2Hz), 6.80-6.83 (2 H, m), 8.23 (1 H, dd, J = 4.6, 1.5 Hz) 17(2) — ESI+:379.4 18 — ESI+: 341.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 0.71 (3 H, d, J= 6.5 Hz), 0.84 (3 H, d, J = 6.5 Hz), 0.91 (3 H, t, J = 7.4 Hz), 1.21 (1H, ddd, J = 14.1, 9.9, 3.7 Hz), 1.35-1.50 (3 H, m), 1.56-1.66 (2 H, m),1.68-1.81 (1 H, m), 2.85-2.97 (2 H, m), 2.99-3.11 (3 H, m), 7.10 (1 H,dd, J = 5.4, 1.7 Hz), 7.13 (1 H, d, J = 1.7 Hz), 8.25 (1 H, d, J = 5.4Hz) 19 — ESI+: 395.3

TABLE 6-3 Ex Syn DATA 20 — ESI+: 361.1 ¹H NMR (400 MHz, MeOH-d₄) δ ppm:0.05-0.11 (2 H, m), 0.41-0.49 (2 H, m), 0.73-0.86 (4 H, m), 0.92 (3 H,d, J = 6.4 Hz), 1.47 (1 H, ddd, J = 14.1, 9.8, 3.7 Hz), 1.58-1.80 (4 H,m), 2.89-2.95 (2H, m), 3.03 (1 H, dd, J = 9.8, 2.6 Hz), 3.42 (2H, s),6.73 (1 H, d, J = 0.9 Hz), 7.38 (1 H, dd, J = 5.7, 0.9 Hz), 8.29 (1 H,d, 15.7 Hz) 21 1 ESI+: 391.3 22 3 ESI+: 297.3 23 3 ESI+: 411.3 24 3ESI+: 475.3 25 3 ESI+: 376.3 26 4 ESI+: 349.3 27 4 ESI+: 389.3 28 4ESI+: 351.3 ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 0.25-0.35 (2 H, m),0.35-0.41 (2 H, m), 0.84 (3 H, d, J = 6.3 Hz), 0.95 (3 H, d, J = 6.3Hz), 1.12 (3 H, s), 1.46 (1 H, ddd, J = 13.9, 9.8, 3.4 Hz), 1.63-1.81 (4H, m), 3.06 (1 H, dd, 19.8, 2.5 Hz), 3.08 (1 H, d, J = 14.4 Hz), 3.22 (1H, d, J = 14.4 Hz), 4.14-4.26 (2 H, m), 6.86 (1 H, dd, J = 6.0, 2.4 Hz),6.95 (1 H, d, J = 2.4 Hz), 8.27 (1 H, d, J = 6.0 Hz) 29 4 ESI+: 351.3 ¹HNMR (400 MHz, MeOH-d₄) δ ppm: 0.01-0.07 (2 H, m), 0.41-0.48 (2 H, m),0.66-0.80 (1 H, m), 0.84 (3 H, d, J = 6.4 Hz), 0.95 (3 H, d, J = 6.4Hz), 1.34-1.51 (3 H, m), 1.61-1.81 (2 H, m), 1.86-1.95 (2 H, m), 3.05 (1H, dd, J = 9.8, 2.8 Hz), 3.07 (1 H, d, J = 13.9 Hz), 3.22 (1 H, d, J =13.9 Hz), 4.07-4.17 (2 H, m), 6.84 (1 H, dd, J = 6.0, 2.4 Hz), 6.93 (1H, d, J = 2.4 Hz), 8.26 (1 H, d, J = 6.0 Hz) 30 4 ESI+: 445.1 31 4 ESI+:449.3 32 4 ESI+: 417.3 33 4 ESI+: 403.3 34 5 ESI+: 392.2 35 5 ESI+:393.2 36 6 ESI+: 447.4 37 6 ESI+: 366.3

TABLE 6-4 Ex Syn DATA 38 6 ESI+: 394.3 39 6 ESI+: 359.1 40 6 ESI+: 397.341 6 ESI+: 365.4 ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 1.00 (3 H, d, J = 6.5Hz), 1.06 (3 H, d, J = 6.5 Hz), 1.51-1.96 (13 H, m), 2.07-2.17 (2 H, m),3.26 (1 H, d, J = 13.8 Hz), 3.51 (1 H, d, J = 13.8 Hz), 3.56-3.69 (1 H,m), 4.89-4.97 (1 H, m), 7.34 (1 H, d, J = 2.6 Hz), 7.38 (1 H, dd, J =7.1, 2.6 Hz), 8.50 (1 H, d, J = 7.1 Hz) 42 6 ESI+: 387.3 43 6 ESI+:403.2 44 6 ESI+: 448.4 45 6 ESI+: 525.3 46 6 ESI+: 401.3 47 6 ESI+:363.4 48 6 ESI+: 456.3 49 6 ESI+: 385.3 50 6 ESI+: 415.4 51 6 ESI+:415.1 52 6 ESI+: 373.3 53 6 ESI+: 361.2 54 6 ESI+: 427.3 55 6 ESI+:353.1 ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 0.89-0.97 (3 H, m), 1.00 (3 H, d,J = 6.4 Hz), 1.06 (3 H, d, J = 6.4 Hz), 1.31-1.52 (7 H, m), 1.63-1.90 (5H, m), 3.25 (1 H, d, J = 13.7 Hz), 3.50 (1 H, d, J = 13.7 Hz), 3.61 (1H, dd, J = 7.5, 5.5 Hz), 4.80-4.90 (1 H, m), 7.36 (1 H, d, J = 2.8 Hz),7.41 (1 H, dd, J = 7.0, 2.8 Hz), 8.50 (1 H, d, J = 7.0 Hz) 56 6 ESI+:365.3 57 6 ESI+: 403.1 58 6 ESI+: 353.3 59 6 ESI+: 367.3 60 6 ESI+:409.4 61 6 ESI+: 407.3 62 6 ESI+: 311.2

TABLE 6-5 Ex Syn DATA 63 6 ESI+: 365.2 64 6 ESI+: 379.2 65 19 ESI+:423.0, 425.0 66 9 ESI+: 365.3 67 9 ESI+: 391.3 68 9 ESI+: 451.2 69 9ESI+: 341.3 70 9 ESI+: 481.0 71 9 ESI+: 479.0, 481.0 72 9 ESI+: 367.3 739 ESI+: 379.4 74 9 ESI+: 421.3 75 9 ESI+: 395.3 76 9 ESI+: 379.4 77 9ESI+: 416.3 78 9 ESI+: 456.2 79 9 ESI+: 393.3 80 9 ESI+: 417.4 81 9ESI+: 419.4 82 1 ESI+: 351.1 83 20 ESI+: 363.2 ¹H NMR (400 MHz, MeOH-d₄)δ ppm: 0.02-0.12 (2 H, m), 0.39-0.51 (2 H, m), 0.67-0.80 (1 H, m), 0.83(3 H, d, J = 6.4 Hz), 0.94 (3 H, d, J = 6.4 Hz), 1.27-1.53 (3 H, m),1.57-1.67 (1 H, m), 1.68-1.80 (1 H, m), 1.80-2.03 (2 H, m), 3.00-3.23 (4H, m), 3.33-3.43 (1 H, m), 4.95-5.08 (1 H, m), 6.74 (1 H, d, J = 5.9Hz), 8.18 (1 H, d, J = 5.9 Hz) 84 9 ESI+: 434.2 ¹H NMR (400 MHz,MeOH-d₄) δ ppm: 0.95 (3 H, d, J = 6.7 Hz), 1.09-1.24 (2 H, m), 1.38-1.55(3 H, m), 1.77-1.85 (2 H, m), 2.08-2.19 (2 H, m), 3.20-3.28 (2 H, m),3.64 (1 H, dd, J = 8.4, 3.3 Hz), 4.40-4.51 (2 H, m), 4.76 (1 H, dd, J =11.7, 3.1 Hz), 6.87-6.93 (1 H, m), 6.97 (1 H, dd, J = 6.3, 2.7 Hz), 7.04(1 H, d, J = 2.3 Hz), 7.54 (1 H, ddd, J = 9.0, 7.8, 3.1 Hz), 8.00 (1 H,d, J = 3.1 Hz), 8.29 (1 H, d, J = 6.3 Hz)

TABLE 6-6 Ex Syn DATA 85 9 ESI+: 389.3 86 9 ESI+: 409.4 87 9 ESI+: 486.488 9 ESI+: 393.3 ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 0.94 (3 H, d, J = 6.6Hz), 1.04-1.21 (2 H, m), 1.39-1.53 (3 H, m), 1.74-1.87 (2H, m),2.08-2.19 (2 H, m), 2.35 (2 H, qt, J = 6.8, 1.3 Hz), 3.09-3.19 (2 H, m),3.32-3.41 (1 H, m), 3.46-3.64 (3 H, m), 3.73-3.92 (1 H, m), 4.42 (1 H,dddd, J = 10.7, 10.7, 4.2, 4.2 Hz), 4.94-5.11 (2 H, m), 5.79-5.89 (1 H,m), 6.89-6.97 (2 H, m), 8.26 (1 H, d, J = 6.2 Hz) 89 13 ESI+: 452.4 9013 ESI+: 364.2 91 13 ESI+: 418.3 92 14 ESI+: 387.3 ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 0.85 (3 H, d, J = 6.6 Hz), 0.92 (3 H, d, J = 6.6 Hz),1.29-1.40 (4 H, m), 1.56-1.69 (1 H, m), 1.74-1.90 (1 H, m), 2.96-3.11 (2H, m), 3.17-3.59 (3 H, m), 5.07-5.16 (1 H, m), 7.19-7.27 (1 H, m),7.27-7.35 (5 H, m), 7.41 (1 H, dd, J = 7.0, 2.4 Hz), 8.34 (2 H, brs),8.61 (1 H, d, J = 7.0 Hz) 93 14 ESI+: 443.1 94 14 ESI+: 393.1, 395.1 9514 ESI+: 379.3 96 15 ESI+: 389.3 97 15 ESI+: 395.2 98 15 ESI+: 403.1 9915 APCI/ESI+: 380.3 100 15 ESI+: 353.3 101 19 ESI+: 375.3

TABLE 6-7 Ex Syn DATA 102 — ESI+: 500.3 103 — ESI+: 369.2 ¹H NMR (500MHz, DMSO-d₆) δ ppm: 0.89 (3 H, d, J = 6.4 Hz), 1.04-1.16 (2 H, m),1.31-1.44 (3 H, m), 1.69-1.75 (2 H, m), 1.97 (3 H, s), 2.01-2.07 (2 H,m), 2.32 (1 H, dd, J = 14.2, 10.5 Hz), 2.89 (1 H, d, J = 13.8 Hz), 2.93(1 H, dd, J = 14.2, 2.4 Hz), 3.03 (1 H, dd, J = 10.5, 2.4 Hz), 3.12 (1H, d, J = 13.8 Hz), 4.35 (1 H, dddd, J = 10.8, 10.8, 4.0, 4.0 Hz), 6.81(1 H, dd, J = 5.8, 2.5 Hz), 6.83 (1 H, d, J = 2.5 Hz), 8.23 (1 H, d, J =5.8 Hz) 104 — ESI+: 399.4 105 — ESI+: 383.2 ¹H NMR (500 MHz, DMSO-d₆) δppm: 0.89 (3 H, d, J = 6.6 Hz), 1.04-1.15 (5 H, m), 1.30-1.44 (3 H, m),1.68-1.75 (2 H, m), 2.01-2.08 (2 H, m), 2.30 (1 H, dd, J = 14.5, 10.8Hz), 2.42 (2 H, qd, J = 7.4, 2.8 Hz), 2.88 (1 H, d, J = 13.8 Hz),2.96-3.06 (2 H, m), 3.12 (1 H, d, J = 13.8 Hz), 4.35 (1 H, dddd, J =10.6, 10.6, 4.0, 4.0 Hz), 6.79-6.86 (2 H, m), 8.23 (1 H, d, J = 5.7 Hz)106 103 ESI+: 397.2 107 103 ESI+: 409.2 108 103 ESI+: 423.3 109 5 ESI+:367.3 110 5 ESI+: 379.2 ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 0.02-0.08 (2 H,m), 0.12-0.18 (2 H, m), 0.40-0.46 (2 H, m), 0.46-0.53 (2 H, m),0.70-0.82 (1 H, m), 0.82-0.93 (1 H, m), 1.50 (2 H, td, J = 6.8, 6.8 Hz),1.71 (2 H, td, J = 6.6, 6.6 Hz), 3.17, 3.19 (2 H, ABq, J = 13.8 Hz),3.42 (1 H, dd, J = 9.0, 3.7 Hz), 3.55-3.62 (3 H, m), 3.88 (1 H, dd, J =10.3, 3.6 Hz), 4.18-4.28 (2 H, m), 7.04 (1 H, dd, J = 6.2, 2.6 Hz), 7.07(1 H, d, J = 2.4 Hz), 8.33 (1 H, d, J = 6.4 Hz) 111 5 ESI+: 353.2 ¹H NMR(400 MHz, MeOH-d₄) δ ppm: 0.12-0.16 (2 H, m), 0.47-0.52 (2 H, m),0.82-0.91 (4 H, m), 0.96 (3 H, d, J = 6.4 Hz), 1.48 (1 H, ddd, J = 13.9,10.0, 3.4 Hz), 1.59-1.81 (4 H, m), 3.07-3.22 (5 H, m), 7.22 (1 H, dd, J= 5.7, 1.9 Hz), 7.28 (1 H, d, J = 1.8 Hz), 8.24 (1 H, d, J = 5.5 Hz) 1125 ESI+: 381.1 113 5 ESI+: 395.1 114 5 ESI+: 369.1

TABLE 6-8 Ex Syn DATA 115 5 ESI+: 381.1 116 5 ESI+: 409.4 117 5 ESI+:435.2 118 5 ESI+: 381.3 119 5 ESI+: 381.2 ¹H NMR (400 MHz, MeOH-d₄) δppm: 0.86 (3 H, d, J = 6.2 Hz), 0.93 (3 H, d, J = 6.6 Hz), 0.96 (3 H, d,J = 6.4 Hz), 1.10-1.24 (2 H, m), 1.35-1.51 (4 H, m), 1.63-1.84 (4 H, m),2.07-2.17 (2 H, m), 3.09 (1 H, d, J = 14.1 Hz), 3.11 (1 H, dd, J = 9.8,2.5 Hz), 3.19 (1 H, d, J = 13.7 Hz), 3.34-3.43 (1 H, m), 7.17 (1 H, dd,J = 5.6, 1.9 Hz), 7.25 (1 H, d, J = 1.5 Hz), 8.23 (1 H, d, J = 5.5 Hz)120 5 ESI+: 407.2 121 5 ESI+: 381.1 122 5 ESI+: 419.3 123 5 APCI/ESI+:377.2 124 5 ESI+: 379.3 125 5 ESI+: 383.3 126 5 ESI+: 395.2 127 5 ESI+:409.3 128 6 ESI+: 411.2 129 9 ESI+: 353.3 130 9 ESI+: 377.1 131 9 ESI+:375.3 132 9 ESI+: 377.2 133 9 ESI+: 401.2 134 9 ESI+: 415.2 135 9 ESI+:399.1 136 103 ESI+: 409.2 137 103 ESI+: 409.2 138 103 ESI+: 397.3

TABLE 6-9 Ex Syn DATA 139 103 ESI+: 409.3 ¹H NMR (400 MHz, DMSO-d₆) δppm: −0.03-0.08 (4 H, m), 0.33-0.45 (4 H, m), 0.67-0.81 (2 H, m),1.30-1.41 (4 H, m), 1.79-1.88 (2 H, m), 2.29-2.37 (1 H, m), 2.46-2.51 (2H, m), 2.91 (1 H, d, J = 13.7 Hz), 2.98-3.08 (2 H, m), 3.16 (1 H, d, J =13.7 Hz), 4.08 (2 H, t, J = 6.5 Hz), 6.82-6.89 (2 H, m), 8.26-8.30 (1 H,m) 140 103 ESI+: 371.3 141 103 ESI+: 355.3 142 103 ESI+: 369.3 143 103ESI+: 369.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 0.00-0.05 (2 H, m),0.37-0.44 (2 H, m), 0.66-0.78 (1 H, m), 1.13 (3 H, t, J = 7.4 Hz),1.28-1.36 (2 H, m), 1.77-1.86 (2 H, m), 2.35 (1 H, dd, J = 14.1, 10.1Hz), 2.44 (2 H, qd, J = 7.4, 1.8 Hz), 2.94 (1 H, d, J = 13.9 Hz), 3.04(1 H, dd, J = 14.3, 2.4 Hz), 3.08 (1 H, dd, J = 10.4, 2.4 Hz), 3.14 (1H, d, J = 13.9 Hz), 4.06 (2 H, t, J = 6.5 Hz), 6.83-6.87 (2H, m),8.24-8.30 (1 H, m) 144 103 ESI+: 383.2 145 103 ESI+: 397.2 146 104 ESI+:411.4

TABLE 7-1 PEx Str 1

2

3

4

5

6

7

8

9

10

11

12

TABLE 7-2 PEx Str 13

14

15

16

17

18

19

20

21

22

23

24

TABLE 7-3 PEx Str 25

26

27

28

29

30

31

32

33

34

35

36

TABLE 7-4 PEx Str 37

38

39

40

41

42

43

44

45

46

TABLE 7-5 PEx Str 47

48

49

50

51

52

53 (1)

53 (2)

TABLE 7-6 PEx Str 54

55

56 (1)

56 (2)

57

58

59 (1)

59 (2)

60

61

62

63

TABLE 7-7 PEx Str 64

65

66

67

68

69

70

71

72

73

74

75

TABLE 7-8 PEx Str 76

77

78

79

80

81

82

83

84

85

TABLE 7-9 PEx Str 86

87

88

89

90

91

92

93

94

95

96

97

TABLE 7-10 PEx Str 98

99

100

101

102

103

104

105

106

107

TABLE 7-11 PEx Str 108

109

110

111

112

113

114

115

116

117

TABLE 7-12 PEx Str 118

119

120

121

122

123

124

125

126

127

128

129

TABLE 7-13 PEx Str 130

131

132

133

134

135

136

137

138

139

140

141

TABLE 7-14 PEx Str 142

143

144

145

146

147

148

149

150

151

152

153

TABLE 7-15 PEx Str 154

155

156

157

158

159

160

161

162

163

TABLE 7-16 PEx Str 164

165

166

167

168

169

170

171

TABLE 7-17 PEx Str 172

173

174

175

176

177

178

179

180

181

TABLE 7-18 PEx Str 182

183

184

185

186

187

188

189

190

191

TABLE 7-19 PEx Str 192

193

194

TABLE 7-20 PEx Str 195 (1)

195 (2)

196

197

198

199

200

201

202

203

TABLE 7-21 PEx Str 204

205

206

207

208

209

210

211

TABLE 7-22 PEx Str 212

213

214

215

216

217

218

219

220

221

TABLE 7-23 PEx Str 222

223

224

225

226

227

228

229

TABLE 7-27 PEx Str 230

231

232

233

234

235

236

237

238

239

TABLE 7-25 PEx Str 240

241

242

243

244

245

TABLE 7-26 PEx Str 246

247

248

249

250

251

TABLE 7-27 PEx Str 252

253

254

255

256

257

258

259

TABLE 7-28 PEx Str 260

261

262

263

264

265

TABLE 7-29 PEx Str 266

267

268

269

270

271

272

273

274

275

276

277

TABLE 7-30 PEx Str 278

279

280

281

282

283

284

285

TABLE 7-31 PEx Str 286

287

288

289

290

291

292

293

294

TABLE 8-1 PEx PSyn DATA 1 — ESI+: 435.2 2 — ESI+: 477.2 3 — ESI+: 254.2[M + Na]⁺ 4 — ESI+: 298.2 [M + Na]⁺ 5 — ESI+: 429.1 6 — ESI+: 234.0,236.0 7 — ESI+: 339.3 8 — ESI+: 551.1 9 — ESI+: 189.1 10 — ESI+: 194.111 — ESI+: 479.3 12 — ESI+: 464.4 13 — ESI+: 462.3 14 — ESI+: 230.1 15 —ESI+: 248.1, 250.1 16 — ¹H NMR (400 MHz, CDCl₃) δ ppm: 3.89 (3 H, s),4.56 (2 H, s), 4.60 (2 H, s), 4.73 (2 H, s), 6.75 (1 H, s), 7.27-7.40 (5H, m), 8.41 (1 H, s) 17 — ESI+: 422.3 18 — ESI+: 276.2, 278.2 19 — ESI+:244.0 20 — ESI+: 260.2 21 — ESI+: 324.3 [M + Na]⁺ 22 — ESI+: 284.1,286.1 23 — ESI+: 565.5 24 — ESI+: 505.4 25 — ESI+: 436.4 26 — ESI+:287.1, 289.1 27 — ESI+: 258.1 28 — ESI+: 214.1 29 — ESI+: 298.2 30 —CI+: 266.1 31 — ESI+: 206.1 32 — ESI+: 384.3 [M + Na]⁺ 33 — ESI+: 409.2

TABLE 8-2 PEx PSyn DATA 34 — ESI+: 479.3 35 — ESI+: 487.3 36 — ESI+:519.2 37 — ESI+: 425.3 38 — CI+: 230.1 39 — ESI+: 318.2 40 — ESI+: 320.341 — ESI+: 197.1 42 — ESI+: 383.2, 385.2 43 — ESI+: 248.1 44 — ESI+:204.0 45 — ESI+: 300.2 46 — ESI+: 487.4 47 — ESI+: 545.1 48 — ESI+:485.4 49 — ESI+: 485.2 50 — ESI+: 449.3 51 — ESI+: 460.2 52 — ESI+:356.1 [M + Na]⁺ 53 (1) — ESI+: 288.2 53 (2) — ESI+: 288.2 54 — ESI+:228.2 55 — ESI+: 543.5 56 (1) — ESI+: 313.2 [M + Na]⁺ 56 (2) — ESI+:313.2 [M + Na]⁺ 57 — ESI+: 503.3 58 — ESI+: 157.0 59 (1) — ESI+: 505.459 (2) — ESI+: 505.4 60 — ESI+: 269.1 61 — ESI+: 345.2 62 — ESI+: 481.463 — ESI+: 372.2 [M + Na]⁺ 64 — ESI+: 242.1 65 — ESI+: 437.4 66 — ESI+:423.4 67 — ESI+: 213.1 68 — ESI+: 357.2, 359.2 69 — ESI+: 446.4 70 —ESI+: 353.3 71 — ESI+: 526.2 72 — ESI+: 443.4 73 — ESI+: 463.2 74 — CI+:167.1 75 — ESI+: 188.1 76 5 ESI+: 481.3 77 1 ESI+: 443.3 78 1 ESI+:459.3 79 1 ESI+: 411.2 80 1 ESI+: 497.1 81 1 ESI+: 423.2 82 1 ESI+:447.2 83 1 ESI+: 421.3 84 1 ESI+: 421.4 85 2 ESI+: 449.4 86 2 ESI+:551.4 87 3 ESI+: 246.1 88 4 ESI+: 278.1 89 4 ESI+: 330.0, 332.0 90 5ESI+: 367.2 91 5 ESI+: 421.3 92 5 ESI+: 556.3 93 5 ESI+: 467.3 94 5ESI+: 435.3 95 5 ESI+: 457.4 96 5 ESI+: 519.1, 521.1 97 5 ESI+: 473.4 985 ESI+: 471.2

TABLE 8-3 PEx PSyn DATA 99 5 ESI+: 435.2 100 5 ESI+: 461.2 101 5 ESI+:419.2 102 5 ESI+: 433.3 103 5 ESI+: 431.2, 433.2 104 5 ESI+: 455.2 105 5ESI+: 473.4 106 5 ESI+: 443.3 107 5 ESI+: 559.2 108 5 ESI+: 551.4 109 5ESI+: 479.4 110 5 ESI+: 381.3 111 5 ESI+: 465.3 112 5 ESI+: 449.3 113 5ESI+: 433.3 114 6 ESI+: 226.1, 228.1 115 6 ESI+: 361.2, 363.2 116 6ESI+: 240.2, 242.2 117 6 ESI+: 262.2, 264.1 118 6 ESI+: 278.2, 280.2 1196 ESI+: 224.1, 226.1 120 6 ESI+: 238.0, 240.0 121 6 ESI+: 260.0, 262.0122 6 ESI+: 278.1, 280.1 123 6 ESI+: 240.0, 242.0 124 6 ESI+: 284.2,286.2 125 6 ESI+: 212.0, 214.0 126 6 ESI+: 278.2, 280.2 127 7 ESI+:158.0 128 7 ESI+: 469.2 129 8 ESI+: 549.3, 551.3 130 8 ESI+: 515.4 131 8ESI+: 519.2 132 9 ESI+: 338.2 133 9 ESI+: 239.1 134 9 ESI+: 255.1 135 9ESI+: 201.1 136 9 ESI+: 215.1 137 9 ESI+: 217.2 138 9 ESI+: 261.1 139 10ESI+: 343.2 140 10 ESI+: 244.0 141 10 ESI+: 260.1 142 10 ESI+: 206.0 14310 ESI+: 220.1 144 10 ESI+: 222.1 145 10 ESI+: 266.1 146 10 ESI+: 233.2147 10 ESI+: 218.1 148 14 ESI+: 258.1 149 21 ESI+: 324.2 [M + Na]⁺ 15023 ESI+: 537.3 151 24 ESI+: 501.4 152 26 APCI/ESI+: 355.1, 357.1 153 27ESI+: 340.2 154 27 ESI+: 338.2 155 27 ESI+: 272.1 156 27 ESI+: 272.3 15728 ESI+: 234.1 158 28 ESI+: 232.2 159 29 ESI+: 258.1 [M + Na]⁺ 160 30ESI+: 204.1 161 33 ESI+: 395.1 162 33 ESI+: 395.1 163 33 ESI+: 381.2 16433 ESI+: 423.3 165 34 ESI+: 491.3 166 34 ESI+: 477.4 167 34 ESI+: 463.2168 34 ESI+: 463.4

TABLE 8-4 PEx PSyn DATA 169 36 EI: 209.8 170 39 ESI+: 272.2 171 40 ESI+:276.3 172 40 ESI+: 274.3 173 41 ESI+: 223.2 174 41 ESI+: 281.1, 283.1175 41 ESI+: 223.1 176 42 ESI+: 325.3 177 42 ESI+: 325.2 178 43 ESI+:286.0, 288.0 179 43 ESI+: 228.1 180 43 ESI+: 228.1 181 45 ESI+: 486.3182 45 ESI+: 526.3 183 45 ESI+: 504.2 184 46 ESI+: 487.2 185 46 ESI+:489.3 186 46 ¹H NMR (400 MHz, CDCl₃) δ ppm: 0.93 (3 H, d, J = 6.3 Hz),1.01-1.17 (2 H, m), 1.38-1.49 (3 H, m),1.73-1.87 (2 H, m), 2.06-2.14 (2H, m), 3.11 (3 H, s), 3.28-3.32 (2 H, m), 3.38 (3 H, s), 4.15-4.26 (2 H,m), 4.36-4.60 (4 H, m), 5.00 (1 H, d, J = 6.7 Hz), 5.14 (1 H, d, J = 6.7Hz), 6.19 (1 H, t, J = 2.1 Hz), 6.62 (1 H, dd, J = 5.9, 2,2 Hz), 6.70 (1H, d, J = 2.2 Hz), 7.40 (1 H, d, J = 2.1 Hz), 7.47-7.50 (1 H, m), 8.25(1 H, d, J = 5.9 Hz) 187 53 ESI+: 237.1, 239.1 188 62 ESI+: 517.3 189 62ESI+: 518.4 190 62 ESI+: 595.4 191 65 ESI+: 435.4 192 65 ESI+: 437.4 19365 ESI+: 537.4 194 68 APCI/ESI+: 425.1, 427.1

TABLE 8-5 PEx PSyn DATA 195(1) — ESI+: 272.1 195(2) — ESI+: 302.1 196 —ESI+: 525.3 197 — ESI+: 450.0, 451.9, 454.0 [M + Na]⁺ 198 — ESI−: 302.1[M − H]⁻ 199 — ESI+: 314.0 [M + Na]⁺ 200 — ESI+: 328.2 [M + Na]⁺ 201 —ESI+: 294.1 [M + Na]⁺ 202 — ESI+: 288.1 203 — ESI+: 539.4 204 — ESI+:555.3 205 — ESI+: 467.1 206 — ESI+: 453.3 207 — ESI+: 229.1 208 — ESI+:399.0, 401.0 209 — ESI+: 278.1 210 — ESI+: 306.2 211 — ESI+: 264.0 212 —ESI+: 300.1 [M + Na]⁺ 213 — ESI+: 272.0 [M + Na]⁺ 214 5 ESI+: 477.2 2157 ESI+: 281.1 216 9 ESI+: 205.1 217 9 ESI+: 203.1 218 9 ESI+: 229.2 21910 ESI+: 210.1 220 10 ESI+: 208.1 221 10 ESI+: 234.1 222 10 ESI+: 234.0223 21 ESI+: 330.1 224 21 ESI+: 366.2 [M + Na]⁺ 225 21 ESI+: 342.1 [M +Na]⁺ 226 21 ESI+: 338.1 [M + Na]⁺ 227 21 ESI+: 336.1 [M + Na]⁺ 228 24ESI+: 521.3 229 24 ESI+: 547.3 230 24 ESI+: 559.3 231 24 ESI+: 517.4 23224 ESI+: 519.4 233 24 ESI+: 523.3 234 24 ESI+: 523.4 235 27 ESI+: 325.2236 27 ESI+: 244.2 237 28 ESI+: 200.1 238 33 ESI+: 425.3 239 33 ESI+:421.3 240 33 ESI+: 395.3 241 33 ESI+: 409.3 242 33 ESI+: 397.4 243 33ESI+: 395.2 244 34 ESI+: 437.3 245 34 ESI+: 449.3 246 35 ESI+: 459.2 24735 ESI+: 499.2 248 35 ESI+: 473.2 249 35 ESI+: 487.4 250 35 ESI+: 475.1251 35 ESI+: 473.1 252 39 ESI+: 304.1 253 41 ESI+: 223.1 254 43 ESI+:228.1 255 61 ESI+: 371.2 256 65 ESI+: 493.3 257 66 ESI+: 521.3 258 66ESI+: 521.3 259 68 ESI+: 427.2 260 5 ESI+: 565.5 261 69 ESI+: 577.4

TABLE 8-6 PEx PSyn DATA 262 69 ESI+: 551.4 263 69 ESI+: 553.4 264 69ESI+: 509.3 265 69 ESI+: 445.4 266 69 ESI+: 471.3 267 69 ESI+: 447.3 26821 ESI+: 342.1 [M + Na]⁺ 269 197 ESI+: 436.0, 438.0, 440.0 [M + Na]⁺ 270197 ESI+: 426.0, 428.0, 430.0 [M + Na]⁺ 271 197 ESI−: 397.9, 399.9,401.9 [M − H]⁻ 272 197 ESI+: 419.9, 421.9, 423.9 [M + Na]⁺ 273 197 ESI+:425.9, 427.9, 429.9 [M + Na]

274 198 ESI+: 290.1 275 198 ESI+: 302.1 [M + Na]⁺ 276 198 ESI+: 298.2[M + Na]⁺ 277 198 ESI+: 296.2 [M + Na]⁺ 278 198 ESI−: 278.0 [M − H]⁻ 279202 ESI+: 296.2 [M + Na]⁺ 280 205 ESI+: 439.2 281 205 ESI+: 467.3 282205 ESI+: 479.3 283 205 ESI+: 453.3 284 205 ESI+: 455.3 285 205 ESI+:453.1 286 5 ESI+: 423.2 287 212 ESI+: 451.2 288 212 ESI+: 465.3 289 212ESI+: 439.3 290 212 ESI+: 451.2 291 212 ESI+: 479.3 292 212 ESI+: 505.4293 212 ESI+: 465.3 294 212 ESI+: 479.3

indicates data missing or illegible when filed

TABLE 9 REx Str DATA 1

ESI+: 365.2 2

ESI+: 365.2

INDUSTRIAL APPLICABILITY

The compound represented by Formula (I) or a salt thereof has inhibitoryactivity against P-LAP, i.e. the AVP-metabolizing enzyme, and maintainsand/or increases an endogenous AVP level to reduce urine production.Such a compound thus is expected to be used as an agent for treatingnocturia, and is also expected to be used as an agent for treating anyother voiding dysfunction or polyuria associated with a decreased AVPlevel, such as pollakiuria, urinary incontinence, and nocturnalenuresis.

1-17. (canceled) 18: A compound represented by Formula (I) or a saltthereof:

wherein: X is S or NR⁴; R⁴ is H, lower alkyl which is optionallysubstituted by one to five halogens, C₃₋₁₂ cycloalkyl, or —C(O)—(C₃₋₁₂cycloalkyl which is optionally substituted by one to five lower alkyls);R¹ is H; C₁₋₁₀ alkyl; -(lower alkylene)-O-(lower alkyl); C₃₋₁₂cycloalkyl which optionally has one to five substituents selected fromthe group consisting of lower alkyl, halogen and —O—(C₃₋₄ alkylene)-;C₅₋₆ cycloalkenyl condensed with a benzene ring; aryl which optionallyhas one to five substituents selected from the group consisting ofhalogen and —O-(lower alkyl); 5- to 6-membered monocyclic heterocyclicgroup which is selected from the group consisting of piperidyl,tetrahydropyranyl, thienyl and pyrazolyl, and which optionally has oneto five substituents selected from the group consisting of lower alkyl,—C(O)-(lower alkyl) and —C(O)—O-(lower alkylene)-aryl; -(loweralkylene)-R¹¹; -(lower alkylene)-O—(C₃₋₁₂ cycloalkyl); -(loweralkylene)-O-aryl or -(lower alkylene)-O-(lower alkylene)-aryl; R¹¹ isC₃₋₁₂ cycloalkyl which is optionally substituted by one to five loweralkyls; aryl which optionally has one to five substituents selected fromthe group consisting of halogen, lower halogenoalkyl, —O-(lower alkyl)and —O-(lower halogenoalkyl) or 5- to 6-membered monocyclic heterocyclicgroup which is selected from the group consisting of piperidyl,tetrahydropyranyl, thienyl and pyrazolyl, and which is optionallysubstituted by one to five lower alkyls; R²'s are the same or differentfrom each other, and are H, lower alkyl, halogen, -(loweralkylene)-aryl, or -(lower alkylene)-O-(lower alkylene)-aryl; R³ isC₁₋₁₀ alkyl which is optionally substituted by one to five halogens;-(lower alkylene)-O-(lower alkyl which optionally has one to fivesubstituents selected from the group consisting of halogen and OH);-(lower alkylene)-O-(lower alkenyl); aryl which optionally has one tofive substituents selected from the group consisting of halogen, CN,-(lower alkylene)-O-(lower alkyl), C₃₋₈ cycloalkyl, aryl which isoptionally substituted by —S(O)₂-(lower alkyl), 5- to 6-memberedmonocyclic heterocyclic group which is selected from the groupconsisting of pyridyl, pyrazinyl, pyrimidinyl and pyrazolyl, and—S(O)₂—(C₃₋₈ cycloalkyl); -(lower alkylene)-(C₃₋₈ cycloalkyl); -(loweralkylene)-(5- to 6-membered monocyclic heterocyclic group which isselected from the group consisting of pyridyl, pyrazinyl, pyrimidinyland pyrazolyl); -(lower alkylene)-O—(C₃₋₈ cycloalkyl); -(loweralkylene)-O-{aryl which optionally has one to five substituents selectedfrom the group consisting of halogen, —O-(lower alkyl), CN and -(loweralkylene)-O-(lower alkyl)}; -(lower alkylene)-O-(5- to 6-memberedmonocyclic heterocyclic group which is selected from the groupconsisting of pyridyl, pyrazinyl, pyrimidinyl and pyrazolyl, and whichoptionally has one to five substituents selected from the groupconsisting of halogen, lower alkyl and lower halogenoalkyl); -(loweralkylene)-O-(lower alkylene)-aryl; -(lower alkylene)-O-(loweralkylene)-(C₃₋₈ cycloalkyl); -(lower alkylene)-S(O)_(n)-(lower alkyl),wherein n is 0, 1, or 2; -(lower alkylene)-S—(C₃₋₈ cycloalkyl); -(loweralkylene)-S-(lower alkylene)-(C₃₋₈ cycloalkyl); -(loweralkenylene)-aryl; or —CH=tetrahydropyranyl; R^(P) is H or a lower alkyl,and R⁶ is H. 19: The compound or a salt thereof according to claim 1,wherein: X is S or NR⁴; R¹ is H; C₁₋₁₀ alkyl; -(lower alkylene)-O-(loweralkyl); C₃₋₁₂ cycloalkyl which optionally has one to five substituentsselected from the group consisting of lower alkyl, halogen and —O—(C₃₋₄alkylene)-; C₅₋₆ cycloalkenyl condensed with a benzene ring, aryl whichoptionally has one to five substituents selected from the groupconsisting of halogen and —O-(lower alkyl); -(lower alkylene)-R¹¹;-(lower alkylene)-O—(C₃₋₁₂ cycloalkyl); -(lower alkylene)-O-aryl or-(lower alkylene)-O-(lower alkylene)-aryl; R¹¹ is C₃₋₁₂ cycloalkyl whichis optionally substituted by one to five lower alkyls or aryl whichoptionally has one to five substituents selected from the groupconsisting of halogen, lower halogenoalkyl, —O-(lower alkyl) and—O-(lower halogenoalkyl); R³ is C₁₋₁₀ alkyl which is optionallysubstituted by one to five halogens; -(lower alkylene)-O-(lower alkylwhich optionally has one to five substituents selected from the groupconsisting of halogen and OH); -(lower alkylene)-O-(lower alkenyl); arylwhich optionally has one to five substituents selected from the groupconsisting of halogen, CN, -(lower alkylene)-O-(lower alkyl), C₃₋₈cycloalkyl, aryl which is optionally substituted by —S(O)₂-(lower alkyl)and —S(O)₂—(C₃₋₈ cycloalkyl); -(lower alkylene)-(C₃₋₈ cycloalkyl);-(lower alkylene)-O—(C₃₋₈ cycloalkyl); -(lower alkylene)-O-{aryl whichoptionally has one to five substituents selected from the groupconsisting of halogen, —O-(lower alkyl), CN and -(loweralkylene)-O-(lower alkyl)}; -(lower alkylene)-O-(lower alkylene)-aryl;-(lower alkylene)-O-(lower alkylene)-(C₃₋₈ cycloalkyl); -(loweralkylene)-S(O)_(n)-(lower alkyl), wherein n is 0, 1, or 2; -(loweralkylene)-S—(C₃₋₈ cycloalkyl); -(lower alkylene)-S-(loweralkylene)-(C₃₋₈ cycloalkyl); or -(lower alkenylene)-aryl; and R^(P) isH.
 20. The compound or a salt thereof according to claim 19, wherein: Xis S. 21: The compound or a salt thereof according to claim 19, wherein:X is NR⁴. 22: A pharmaceutical composition comprising a compound or asalt thereof according to claim
 18. 23: A method of treating nocturiacomprising administering an effective amount of a compound or a saltthereof according to claim 18 to a subject in need thereof.